Dialysis Patients' Fluid Overload, Antihypertensive Medications, and Obesity

Abstract

Overhydration (OH) is both a major etiology of hypertension in hemodialysis patients and a serious risk factor for mortality. We investigated the association of multiple variables and OH. This is a cross-sectional study of prevalent hemodialysis patients examining the predialysis hydrational status with a portable bioimpedance apparatus to measure the degree of hydration. We completed our study in 79 patients. Patients were overhydrated by 2.6 ± 2.4 L. The mean medication count was 2.4 ± 1.5, and 50.7% had diuretics. We found a significant correlation between OH and systolic blood pressure (r = 0.39; p = 0.0006), each liter of OH generating 3.6 mm Hg. We also found a positive correlation between the use of diuretics and OH (p = 0.003, two-tailed Student's t test) but no correlation between OH and body weight (r < 0.0001; p = 0.99), body mass index (r = −0.17), age (r = 0.089), and vintage (r = 0.05). For every 10% increase in body fat, OH decreased by 1.2 L; residual urine output gave no protection from OH (r = 0.077) and did not correlate with blood pressure (r = 0.01). Overhydration is strongly associated with the use of antihypertensive medications and the use of diuretics in this dialysis population. Obesity seems to afford some protection from OH.

Hypertension and hypercholesterolemia are well-established, modifiable cardiovascular risk factors in the general population. The applicability of these risk factors have raised many questions when applying these risk factors in the dialysis population, and a consensus is much harder to generate regarding these risk factors than for those in the general population. The K/DOQI guidelines and European guidelines have no recommendation for hypercholesterolemia in dialysis patients. For example, the evidence supporting cholesterol lowering is lacking, and the use of statin drugs have failed to produce the benefits seen in the nondialysis population in recent prospective randomized trials. Hypertension has also been called into question as a risk factor,^1–4 and some will argue that it remains an important cardiovascular risk factor^5–7 and even a sign of dialysis adequacy^8,9 while others have argued to the contrary.⁷ Although there is an apparent contradiction in these arguments, it seems that the study by Wizemann et al.¹⁰ may help resolve the paradox, namely that it may be true that hypertension is a risk factor in the dialysis population mostly as a reflection of volume overload. If volume overload is controlled, then the hypertension is mostly eliminated or treated and high blood pressure readings in and of itself may not be as important. Volume overload or extracellular fluid excess may be a more significant cardiovascular risk factor, not blood pressure. Whichever may be the greater risk factor, hypertension or volume overload, reduction of extracellular fluid certainly does reduce blood pressure and it may improve dilated cardiomyopathy. Control of extracellular fluid, however, requires an estimate or measurement of its volume. This fluid volume can be measured by various means including the measurement of B-type natriuretic peptide level and two- dimensional measurement of the inferior vena cava, or this fluid can be monitored by continuous hematocrit monitoring to control the physiologic disappearance of excess fluid while on dialysis.

Bioimpedance is another method of measuring fluid spaces^11–14 using a technique relying on the behavior of low voltage electricity. As the electric current travels through the various body compartments, differences in resistance (impedance) can be detected. Low frequency currents cannot cross cell membranes and will only travel through the extracellular fluid compartment (ECF). High frequency currents on the other hand can travel through both intra- and extracellular compartments. The software of bioimpedance monitors can differentiate between the various compartments and measure fluid compartments as well as calculate other compartments from the input data such as patient weight, height, gender, and age. Whole body bioimpedance analyzers and segmental analyzers have been validated in various studies to track fluid removal of dialysis patients.

We designed a cross-sectional study in which we measured the extracellular fluid compartment, the degree of overhydration (OH), and fat compartment by whole body (wrist-to-ankle) bioimpedance. We conducted this study to evaluate the relationship of the degree of hydration, blood pressure, blood pressure medications, and the utility of controlling blood pressure by means of antihypertensive medications.

Methods

This is an Ethical Committee-approved (Institutional Review Board) cross-sectional study of 79 chronic, prevalent hemodialysis patients who receive their hemodialysis at the medical school-associated dialysis unit in Budapest, Hungary. Acutely ill patients, patients who had limb amputations, local extremity edema, or ulceration, or those who declined participation were excluded from the study. We collected their monthly laboratory data and their demographic data (Table 1) from the medical records. We prospectively measured their predialysis fluid volumes and degree of OH by a portable whole body, ankle-to-wrist bioimpedance monitor (BCM—Body Composition Monitor; Software version 3.2; Fresenius Medical Care Ag., Bad Homburg, Germany). The instrument calibration was checked and verified monthly as prescribed by the manufacturer. The patients were asked to lay flat just prior to their hemodialysis session in their reclining dialysis chair. Disposable electrode strips provided by the manufacturer were placed on the dorsal surfaces of the hand and foot, at the wrist and distal metacarpal bones over the knuckles, and at the mid-ankle and distal metatarsal bones, respectively. The patients' age, gender, height, weight, and blood pressure were fed into the BCM and then assuring that no contacts were made between the patient and conductive surfaces and far from any potential instruments with an electric field—such as dialysis machines, electrocardiogram (EKG) monitors, and television sets—in a room separate from the place where their dialysis session was to be delivered, the measurements were recorded. BCM measurements were performed in a separate room, purely for our convenience; to perform accurate BCM measurements, it is not necessary to use a separate room. The BCM instrument returns measurements on OH in liters (L), total body water (TBW) in liters, extracellular water (ECW) in liters, urea distribution volume (V) in liters, intracellular water (ICW) in liters, lean tissue mass (LTM) in kg/%, and body mass index (BMI) in kg/m². Overhydration is a part of the extracellular volume, measured by a model developed by Hanai; the OH is calculated on measurement values, using a the model of two conductive fluids.^15,16 Body fat is calculated by the BCM instrument based on the internal algorithms set by the manufacturer.

Table 1: Demographic Data and Measurements

Prior to initiating a clinical study with the use of BCM hydration, blood pressure and antihypertensive medications were only managed based on clinical impression and the clinical signs and symptoms of volume excess or deficit. Laboratory testing was performed in the clinical laboratory of Semmelweis University School of Medicine (Budapest, Hungary) accredited laboratory meeting all clinical and scientific standards and calibrations required by the State. These laboratory tests were collected mid-week for the dialysis patients' monthly laboratory monitoring. The blood pressure measurements included in the study were collected at the beginning of the dialysis session.

Calculations were performed by mathematicians at the Louisiana State University Shreveport, Louisiana. Correspondence of clinical data was performed using GraphPad Prism (GraphPad Software, Inc.) software using linear regression analysis, Student's t test as appropriate. Multivariate regression analysis was also performed using SPSS (IBM Corporation, Somers, NY).

Results

We had 79 patients in our database. One was excluded as he had acute rather than chronic renal failure and two additional patients did not have a complete set of data. The mean age was 60.7 ± 16.9 years and 49.3% of the patients were male; 30.7% of the patients were diabetic and 78.7% had an arteriovenous fistula as their dialysis access. There were only 22 (29.3%) patients who were managed with no or one antihypertensive medication and 11 (14.7%) patients had five or six medications; the mean medication count was 2.4 ± 1.5 with a 50.7% prevalence of diuretic use. The patient population had a mean vintage of 66.5 ± 57.1 months (range, 2–312 months) and a residual urine output of 442 ± 521 ml/day. The difference in residual urine volume between those with 0 or 1 antihypertensive medication versus the rest of the cohort was nonsignificant (390 ± 550 ml/day vs. 476 ± 506 ml/day; p = 0.48). On the average, patients were overhydrated by 2.6 ± 2.4 L and had a percent body fat of 36.4 ± 11.6 kg. The mean blood pressure and mean arterial pressure (MAP) were 132/75 ± 22/10 and 94 ± 13 mm Hg, respectively. We found a significant correlation between OH and systolic blood pressure (r = 0.39; p = 0.0006) with each liter of OH generating 3.6 mm Hg. This positive correlation between the number of antihypertensive medications and the degree of OH held true even when those patients with no blood pressure medications and those with five or more medications were excluded (r = 0.33; p = 0.047). This, however, falls below our expectations which could be explained with the possible inaccuracies involved with the blood pressure measurements of clinical practice even though, admittedly, there are many other pathophysiological processes at play in the dialysis population. We also found a positive correlation between the use of diuretics and OH (p = 0.003, two-tailed Student's t test); diuretics provided no protection from OH. We found no evidence for OH having a relation to body weight (r < 0.001; p = 0.99), body mass index (r = 0.17), age (r = 0.08), and vintage (r = 0.04). When obesity is expressed in percent body fat, it had a very significant negative correlation (r = −0.53; p < 0.0001). p” to “r” in the term “p = −0.52” is appropriate. —With every 10% increase in body fat, there is a decrease of OH by about 1.2 L. Such protection from OH could not be demonstrated by a correlation between the residual urine output and OH (r = 0.07); interestingly, residual urine output did not correspond with blood pressure readings (albeit, admittedly inaccurate blood pressure readings; r = 0.01).

The multivariate regression analysis revealed similar results. Factors associated with OH were the total number of antihypertensive medications (standardized coefficient, 0.673; p < 0.001), percent body fat (standardized coefficient, −0.492; p = 0.002), and serum albumin (standardized coefficient, −0.191; p = 0.051).

Discussion

The underlying etiology of hypertension in dialysis patients is intravascular volume overload,¹⁷ as a result of increased extracellular salt and water. Slow removal of excess salt and water during the dialysis session treats hypertension in more than 90% of dialysis patients.¹⁸ Control of hypertension is thus primarily achieved with controlling the ECW preferably with longer dialysis sessions.¹⁹ Antihypertensive medications have also been shown in a cross-sectional study to be ineffective in controlling blood pressure because the achieved blood pressure was successively higher as the number of antihypertensive medications was escalated.²⁰ Tapolyai et al. speculated that the reason hypertension control could not be achieved was the counterproductive effect of antihypertensive medications; a lower blood pressure is achieved faster during the dialysis session, hypotension is reached earlier, and ultrafiltration is halted. This hypothesis, that antihypertensive medications are associated with fluid retention, is confirmed in this present study. Our study shows that the total number of antihypertensive medications exacerbates fluid retention (r = 0.54; p < 0.0001; Figure 1) in a graded fashion, and this relationship is preserved even when data of those who were on no blood pressure medications or those with five or more blood pressure medications are excluded. Each additional medication is associated with about one extra liter of excess ECW. The regression analysis confirms these results with a robust degree of significance (<0.001). However, the number of antihypertensive medications do not affect achieved, predialysis blood pressure (r = 0.09; p < 0.42). Prior to these measurements, dry weight reduction was achieved based on clinical impression without any set protocols. Patients' medications were usually carried over from their predialysis times or continued from their hospitalizations. Once we obtained the BCM data, we started to slowly reduce the patients' estimated dry weight and we were successful in reducing both the number of antihypertensive medications and patients' blood pressure.

Figure 1.: The number of antihypertensive medications has a strong relation to the degree of overhydration as measured by bioimpedance. Linear regression analysis: n = 76, p < 0.0001, r = 0.54 and multivariate regression analysis coefficient: 0.673, p < 0.0001.

Interestingly, the use of diuretics in this dialysis population seems to exacerbate fluid excess as well (Figure 2), perhaps by giving a false sense of security to patients about the need for fluid restriction or a false sense of security to the medical team to be less aggressive with ultrafiltration. The interdialytic weight gain, however, does not seem to have a correlation with OH (r = 0.14). Multivariate regression analysis did not reveal a better control of OH when diuretics (p = 0.081) are used despite that close to half of the patient population (50.7%) was taking diuretics (furosemide). The use of diuretics cannot be advocated in dialysis patients for fluid control based on these data although results may be different if a strict weight and blood pressure protocol were in followed.

Figure 2.: In the presence of diuretics D (+), the degree of overhydration is significantly greater than in its absence D (−). p = 0.003, two-tailed Student's t test.

The writers of the cardiovascular section (Section II, guideline 12) in the KDOQI²¹ guidelines speculate that “the lack of a significant correlation between blood pressure and cardiovascular events in dialysis patients” may be due to an inhomogeneous case mix with patients who have chronic hypotension due to heart disease. Wizemann et al.¹⁰ have shown that “...hydration state is an important and independent predictor of mortality in chronic HD patients secondary only to the presence of diabetes.” Considering that dialysis patients' hypertension is a result of fluid excess, this becomes an important “side-effect” of antihypertensive medications. It is the limitation of this study that this is a cross-sectional study and causation cannot be concluded from cross-sectional study designs; however, a strong association with a high degree of correlation is noted between blood pressure medications and fluid overload. Antihypertensive medications alone not only are insufficient to adequately control blood pressure in hemodialysis patients²² but they seem to impede²⁰ such efforts. Antihypertensive medications including diuretics appear as risk factors for fluid retention. The goal that²³ dialysis should be performed to achieve fluid removal without antihypertensive drugs is countered if antihypertensive medications are escalated when hypertension is detected.

We also found that obesity is not associated with fluid retention when OH is correlated with body weight (r = <0.01) or BMI (r = 0.1). Percent body fat, however, does have a reversed relationship with OH; the equation of the linear regression line between percent body fat and OH is y = −0.128x + 7.041 (r = 0.53; p < 0.0001; Figure 3). The multivariate model also confirms this negative association (standardized coefficient, −0.492; p= 0.002). This is in line with our clinical observation that thinner, smaller patients not only have a greater absolute amount of extra fluid but relative volume excess as well. Our observation could perhaps also add to the discussion of reverse epidemiology of obesity and outcome in the maintenance dialysis population, namely that obesity seems to give a survival advantage.²⁴ The explanation may be that patients with a greater body fat and higher BMI have less fluid retention. Residual urine output has no relationship (r = 0.1) with OH, and we found no correlation (r = 0.04) between dialysis vintage or patient age (r = 0.08) and OH (Figure 4). Interdialytic weight gain or percent interdialytic weight gain offered little (r = 0.04) to associate OH (standardized coefficient, 0.189; p = 0.851). Therefore, it is not the amount of fluid patients gain that cause OH nor the amount of urine output that determines volume overload, but perhaps the amount of ultrafiltration that could not be achieved because of antihypertensive medications; perhaps antihypertensive medications exacerbate volume overload by preventing a safe, hypotension-free ultrafiltration.

Figure 3.: Percent body fat and fluid excess: an inverse relationship indicating that a greater body fat is associated with significantly less fluid retention. p < 0.0001, r = −0.53; multivariate regression analysis coefficient: −0.492, p = 0.002.

Figure 4.: Residual urine volume and fluid excess: no relationship could be shown between residual urine volume and the degree of overhydration. n = 75, r = 0.007, p = 0.48; multivariate regression analysis coefficient: 0.009, p = 0.93.

Finally, the utility of the portable BCM instrument is demonstrated by the clinically actionable measurements and data it can provide. Whole body bioimpedance with BCM was found to be one of the most accurate methods to assess hydration by others as well^25,26 and a reliable guide of volume management²⁷ that improved cardiac function and blood pressure. Monitoring extracellular volume by this method makes the estimation of dry weight²⁸ evidence based and may improve blood pressure and volume control.