Cardiovascular disease is the leading cause of death among patients with ESRD (1). Left ventricular hypertrophy (LVH) (2–6) and chronic inflammation (7,8) are independent risk factors for cardiovascular death among patients who receive maintenance hemodialysis. Interventions that improve these factors may decrease the risk for death. Development and progression of LVH in patients with ESRD is complex and often multifactorial; pathogenetic factors include volume overload, creation of arteriovenous (AV) fistulae, anemia, and pressure overload (9–13). Potential causes of chronic inflammation in patients who receive maintenance dialysis include dialyzer incompatibility, acidosis, oxidative stress, dialysate contamination, occult infection of clotted AV grafts, and kidney allograft loss among patients with a previous transplant (7,14–18).
Given the persistently poor prognosis associated with chronic dialysis, there is ongoing interest about whether modifications of standard hemodialysis regimens, such as increasing the time, dose, and/or frequency of hemodialysis, can improve outcomes. The HEMO study demonstrated no benefit on risk for death with an increased dose of hemodialysis or increased flux of the membrane (19). However, altering the frequency of hemodialysis was not evaluated. Previous cohort studies of more physiologic strategies of hemodialysis, including nocturnal home hemodialysis and short daily hemodialysis, have suggested potential beneficial cardiovascular effects (20–31). Short daily hemodialysis (six sessions per week with 1.5 to 3.0 h per session) aims at improved, more physiologic solute and fluid removal. Previous uncontrolled studies of short daily hemodialysis have reported improved BP control, higher hemoglobin levels, regression of LVH, and decreased risk for hospitalization (20–28). Nocturnal home hemodialysis, a modality that significantly increases both the time and the frequency of dialysis, has been reported to induce regression of LVH, increase vagally mediated heart rate variability during sleep, decrease nocturnal hypoxemia, and improve phosphorus control in selected patients (29–31). Thus, these forms of hemodialysis may have advantages over conventional hemodialysis.
Recently, preliminary data suggest that short daily dialysis may also be associated with improved phosphorus control (32). Poor control of phosphorus in patients with ESRD is recognized as an important cardiovascular risk factor (33,34), and hyperphosphatemia itself was linked recently to LVH in an animal model (35). This suggests that short daily hemodialysis may have benefits on LVH beyond better control of BP, volume overload, and anemia. However, because the role of short daily hemodialysis in reducing cardiovascular morbidity and mortality remains uncertain, we performed a prospective clinical trial to examine the effects of short daily hemodialysis compared with conventional hemodialysis on two important risk factors for cardiovascular outcomes in the ESRD population: LVH and markers of chronic inflammation.
Materials and Methods
All participants were adult patients who were receiving maintenance hemodialysis at Dialysis West at the Texas Diabetes Institute (San Antonio, TX). During January 2003, all participants were enrolled in the study and were followed for 12 mo. The Bexar County Hospital District approved the prospective enrollment of only 26 patients in the short daily hemodialysis program. The only eligibility criterion was willingness to participate in the short daily hemodialysis program, and no patient was excluded. A total of 108 patients were screened for enrollment, and short daily hemodialysis was offered to all patients.
Spaces were offered consecutively to 36 patients who agreed to participate on a voluntary basis until 26 enrollees was reached. At that time, 51 contemporary conventional hemodialysis patients from the original 108 eligible patients were selected on the basis of similar baseline characteristics (age, gender, cause of renal disease, comorbidity burden, vascular access, medications, and time on dialysis). The study protocol was approved by the institutional review board, and written informed consent was obtained from all study participants.
A prospective, nonrandomized, controlled study of short daily hemodialysis (6 sessions per week of 3 h each) versus conventional hemodialysis (3 sessions per week of 4 h each) was performed with a follow-up period of 12 mo. Dialysis treatments in both groups used polysulfone, high-flux dialyzers (Optiflux 2000; Fresenius, Lexington, MA); blood flows were 400 ml/min, and dialysate flows were 800 ml/min. Adjustments were made to dialysate bath; dry weight; and medications, including erythropoietin, phosphate binders, vitamin D sterols, and intravenous iron, by the treating nephrologists to achieve Kidney Dialysis Outcomes Quality Initiative guidelines for control of BP, anemia, and secondary hyperparathyroidism (36). Aside from the increased frequency of dialysis visits in the short daily hemodialysis group, there was no difference in the frequency of clinic visits or monitoring of laboratory values in either group. All patients were treated with low-dose (81 mg/d) aspirin, statins and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers as tolerated. At presentation, patients were stratified into three categories according to age, diabetes, and preexisting comorbidities as defined by Khan et al. (37) and recently validated on dialysis patients (38): Low risk, <70 yr of age without comorbidities or diabetes; moderate risk, between 70 and 80 yr of age, with diabetes or significant cardiovascular pathology; high risk, >80 yr of age, or >70 plus diabetes, or <70 plus diabetes plus significant cardiovascular pathology or dysfunction of more than two organs or cancer, except skin cancer.
A primary outcome was the change in echocardiographic LVH parameters. Baseline and 12-mo follow-up transthoracic echocardiographic studies were performed by the same cardiologist, in a blinded manner, using standardized protocols (39). A separate echocardiographic cardiologist, who was blinded to group and treatment status, independently reviewed and evaluated all echocardiograms. Neither of the cardiologists who reviewed the echocardiograms had any formal association with the study or was aware of the hypotheses being tested. Echocardiograms were obtained predialysis in the short daily hemodialysis group and on the day off dialysis in the conventional hemodialysis group. Using standard methods, readings were taken in the lateral decubitus position using M-mode and Doppler techniques. Left ventricular mass index (LVMI) was calculated using the Devereux formula (39). Aortic valve calcification was also scored as none, mild, moderate, or severe. From previous quality control measures of the echocardiography laboratory used in this study, the intrarater variability for the cardiologists who read the echocardiograms in the study is reported as <5%.
The other main outcome included measures of chronic inflammation. Plasma ultrasensitive C-reactive protein (CRP) and homocysteine levels were measured at baseline, 6 mo, and 12 mo. CRP was measured by ultrasensitive assay (normal range 0 to 1.0 mg/dl), and homocysteine (normal range 4 to 10 μmol/L) was measured by chemiluminescence. Values given are the mean of several repeated measurements. Erythropoietin resistance index (ERI), another putative marker of inflammation in dialysis patients, was calculated by weekly erythropoietin dose (units)/body weight in (kg)/hemoglobin concentration (g/dl) (14). Routine blood counts and metabolic profiles were also measured monthly and assessed as secondary outcomes.
A secondary outcome of interest was peripheral vascular calcification because patients who receive maintenance dialysis are at increased risk for accelerated tissue and vascular calcification. At 12-mo follow-up, radiographs of the feet and hands were performed to assess point prevalence of the severity of peripheral vascular calcification (40). A single radiologist, who was blinded to treatment modality, scored the severity of vascular calcification according to the following scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. A second radiologist also independently reviewed the studies in a blinded manner, and in the case of disagreement between the first two reviewers, a third radiologist reviewed the study and adjudicated the case. None of the radiologists who reviewed the x-rays had any formal association with the study, and none was aware of the hypotheses being tested.
All statistical analyses were conducted using SAS Version 9.1 (SAS Institute Inc., Cary, NC). A two-sided P < 0.05 was considered statistically significant. Distributions of each variable were examined, and logarithmic transformations were made where appropriate. Continuous variables are presented as either means with SD or medians with interquartile ranges. Standard parametric or nonparametric tests were used to compare continuous variables between groups. Analysis of covariance was performed to adjust the results for intact parathyroid hormone (PTH). χ2 or Fisher exact test was performed to compare categorical variables between groups. McNemar test was performed to examine differences between treatment groups in the change in dichotomized CRP level (i.e., CRP ≥0.5 versus <0.5 mg/dl) from baseline to the end of follow-up. Differences between groups in secondary outcome variables at baseline and at 6- and 12-mo follow-up were also examined using appropriate tests for continuous and categorical variables described above, including a linear test for trend over time. Pearson or Spearman correlations were used to investigate relations between left ventricular mass and other variables. Multivariable linear regression analyses were performed to examine the relationship between dialysis regimen and LVMI and CRP level, after controlling for potential confounders.
Of 108 eligible patients, 77 were enrolled in the study, with 26 in the short daily hemodialysis group and 51 in the conventional hemodialysis group. All enrolled participants completed the 12-mo follow-up, with no dropouts or deaths. Demographic and baseline clinical and laboratory characteristics were not significantly different between the short daily hemodialysis and conventional hemodialysis groups, except for lower calcium, higher phosphorus, higher calcium × phosphorus product, and lower hemoglobin levels in the short daily hemodialysis group (Table 1).
At baseline, LVMI was not significantly different between short daily hemodialysis and conventional hemodialysis groups (Table 1). At 12-mo follow-up, LVMI decreased by 30% (154 ± 33 to 108 ± 25; P < 0.0001) in the short daily hemodialysis group (Figure 1). In contrast, LVMI did not change significantly in the conventional hemodialysis group during the same period (Figure 1). In unadjusted linear regression models, receipt of short daily hemodialysis was associated with a notable decrease in LVMI (β = −51.6, P = 0.008). Other univariate predictors of reduced LVMI included percentage change in serum phosphorus (β = 0.52, P = 0.01), percentage change in calcium × phosphorus product (β = 0.69, P = 0.04), and percentage increase in weekly ultrafiltration (β = −0.08 per liter increase, P = 0.02). In multivariable linear regression, receipt of short daily hemodialysis (β = −41.63, P = 0.03) and percentage decrease in phosphorus level (β = −0.12, P = 0.04) were the only significant predictors of a decrease in LVMI; an increase in weekly ultrafiltration (β = −0.06, P = 0.05) and the interaction between treatment group and vitamin D (paricalcitol; β = −0.06, P = 0.05) were of borderline statistical significance. To analyze further the role of different variables that may have contributed to a decrease in LVMI, we performed a Pearson correlation coefficient analysis in all patients in which LVMI decreased regardless of treatment group assignment. We found that in the subgroup of patients who experienced a decrease in LVMI, the significant predictors included serum phosphorus level (r = 0.56, P = 0.03; Figure 2), serum albumin (r = 0.60, P = 0.04), and total serum bicarbonate (r = −0.68, P = 0.004). In addition, at 12-mo follow-up, median left ventricular end-diastolic and end-systolic diameters as well as stroke volume index significantly decreased in the short daily hemodialysis group (Table 2). By contrast, these echocardiographic parameters did not change in the conventional hemodialysis group (Table 2). Left ventricular posterior wall thickness and interventricular septal thickness did not change significantly in either the short daily hemodialysis group or the conventional hemodialysis group at the end of follow-up (Table 2).
Inflammatory and Other Biomarkers
At baseline, there were no significant differences in CRP levels, erythropoietin doses, and serum albumin and plasma homocysteine levels between short daily hemodialysis and conventional hemodialysis groups (Table 3). However, hemoglobin level was lower and ERI was higher in the short daily hemodialysis group than in the conventional hemodialysis group (Table 3). There was a decrease in median CRP levels between baseline and 6- and 12-mo follow-up (P < 0.01 for trend), with a 95% reduction at 12-mo follow-up (Table 3). Furthermore, the proportion of patients with normal CRP levels increased from 19.1 to 61.0% (P = 0.006) between baseline and the end of follow-up in the short daily hemodialysis group (Figure 3). After adjustment for change in ERI and other potential confounders, receipt of short daily hemodialysis was independently associated with a 12-mo change in CRP level (β = −0.01 P = 0.003). Percentage change in ERI was positively correlated with percentage change in CRP level (Figure 4). Median ERI decreased by 46% at 12 mo of follow-up in the short daily hemodialysis group (Table 3). Hemoglobin and albumin levels also increased in the short daily hemodialysis group during follow-up, with a significant temporal trend in increasing hemoglobin noted across the three time points (P < 0.01 for trend; Table 3). Short daily hemodialysis was associated with increased hemoglobin levels compared with conventional hemodialysis, even after controlling for differences in baseline hemoglobin level and other relevant confounders (P < 0.001). By contrast, in the conventional hemodialysis group, there was no change during follow-up in CRP level, hemoglobin level, erythropoietin dose, ERI, and albumin level. Plasma homocysteine levels significantly increased in both the short daily hemodialysis and conventional hemodialysis groups.
Dialysis Parameters and BP Control
Short daily hemodialysis significantly increased cumulative dialysis dose and ultrafiltration (Table 4). Furthermore, short daily hemodialysis was associated with a reduced systolic BP and pulse pressure at 6 mo (145 ± 13.0 to 139 ± 9.63 mmHg; P < 0.05), but at 12 mo, there were no significant differences compared with baseline values (Table 4). In the conventional hemodialysis group, there were no significant changes in BP, pulse pressure, pre- and postdialysis weights, and ultrafiltration at 6 or 12 mo.
Regulation of Mineral Metabolism
At baseline, the short daily hemodialysis group had lower serum calcium levels and higher phosphorus and calcium × phosphorus product (Table 5). At 12-mo follow-up, receipt of short daily hemodialysis was associated with significantly improved levels of calcium, phosphorus, calcium × phosphorus product, and PTH levels. In multivariable linear regression models that controlled for baseline levels and other confounders, short daily hemodialysis was associated with significant increases in calcium (P < 0.01) and decreases in phosphorus (P < 0.001) and calcium × phosphorus product (P < 0.01) as compared with conventional hemodialysis. After 12 mo of follow-up in the short daily hemodialysis group, there was a 6.3% increase in serum calcium (P < 0.001), 32.9% decrease in serum phosphorus (P < 0.0001), 28.6% decrease in calcium × phosphorous product (P < 0.001), and 41.7% decrease in median PTH level (P < 0.001; Table 5, Figure 5). Median paricalcitol dose increased by 83% in those who received short daily hemodialysis (P < 0.05) at 12 mo, whereas the use of phosphate binders decreased substantially in the short daily hemodialysis group, with 70% of patients off phosphate binders at the end of the study period. Sevelamer dose was not significantly different from baseline to 12 mo in the patients who continued taking sevelamer (Table 5). Furthermore, the use of calcium acetate decreased significantly at 12 mo among the patients who continued to take these medications. By contrast, in the conventional hemodialysis group, there was no significant change in serum calcium level, serum phosphorus level, or calcium × phosphorus product at the end of follow-up. After 12 mo, there was a 20.9% decrease in median PTH levels (P < 0.05) in the conventional hemodialysis group, with no significant changes in calcitriol, paricalcitol, sevelamer, or calcium acetate doses (Table 5).
Point Prevalence of Peripheral Vascular and Valvular Calcification
At the end of 12-mo follow-up, the point prevalence of moderate or severe vascular calcification by radiography was significantly lower in the short daily hemodialysis group compared with the conventional hemodialysis group for feet (23.5 versus 69.0%, respectively; P = 0.005) and hands (17.7 versus 58.6%, respectively; P = 0.01). There was no significant difference between the groups in the prevalence of mild, moderate, or severe aortic valve calcification at 12 mo in short daily hemodialysis (17.7%) compared with conventional hemodialysis (25.0%; P = 0.51) patients.
We found that compared with a conventional hemodialysis regimen, receipt of short daily hemodialysis with high-flux, biocompatible membranes was associated with a reduction in LVH and improvement in inflammatory and related biomarkers at 12 mo. These end points are of clinical interest because of their association with poor cardiovascular outcomes among patients who receive maintenance hemodialysis (2–8,17,33,34).
LVH is a powerful predictor of poor cardiac outcomes in chronic dialysis patients (4–6), and it is present in ESRD patients at rates far higher than in the general population (2–6). In patients with ESRD and an LVMI >125 g/m2, 5-yr survival was 20%, compared with 50% in those who had an LVMI <125 g/m2 (4). LVH is an adaptive response to increased cardiac workload that has short-term beneficial effects on cardiac function but long-term, detrimental consequences (11). In the short term, LVH enhances the work capacity of the heart, while keeping tensile stress stable; whereas over time, these responses become maladaptive. The pathogenesis of LVH is a complex process that involves multiple factors. Pressure overload results in addition of sarcomeres in parallel (maintaining left ventricular radius at the expense of increasing wall thickness), termed concentric hypertrophy. Volume overload leads to addition of sarcomeres in series (leading to enlargement of the left ventricular chamber) (11). The nature of LVH in ESRD includes characteristics of both of these processes (10,11). The clinical factors in the setting of kidney disease and dialysis that predispose to the development of LVH include volume overload, creation of AV fistulae, anemia, and pressure overload (9–13). Pressure overload is a complex interaction that involves increases in both afterload and arterial stiffness (11). In summary, LVH is a complex disorder with many causes in ESRD and unfavorable effects on cardiovascular outcomes.
Our results show a significant decrease in LVMI associated with short daily dialysis compared with conventional hemodialysis (Figure 1). Several uncontrolled studies of short daily hemodialysis (20,21) and nocturnal home hemodialysis (31) also have suggested reductions in LVH. However, to our knowledge, our study is the first to demonstrate a significant reduction in LVMI in a controlled manner comparing patients who received short daily hemodialysis or conventional hemodialysis in the setting of maximal guideline-based medical care.
A key finding is that the observed reduction in LVMI in the short daily hemodialysis group occurred despite no significant changes over time in BP control, suggesting that factors beyond better BP control likely are involved in the maintenance or progression of LVH in these patients. In addition to receipt of short daily hemodialysis, increases in ultrafiltration and improved control of phosphorus levels were found to be independent predictors of a reduction in LVMI. Of note, epidemiologic studies have shown that elevated phosphorus level and calcium × phosphorus product are associated with increased risk for cardiovascular death in patients who are on maintenance dialysis (33,34,41). Our multivariable analyses coupled with the observed changes in left ventricular geometry and stroke volume index (Table 2) provide insight into how short daily dialysis may contribute to a reduction in LVH.
Reductions in left ventricular end-diastolic and end-systolic diameters seen in the short daily dialysis group without significant changes in posterior wall or interventricular septal wall thickness (Table 2) likely reflect improvements in extracellular fluid volume control, consistent with the finding that increased ultrafiltration was associated with reduction in LVMI. In addition, stroke volume index decreased in the short daily dialysis group (Table 2) with no change in ejection fraction. This reduction in stroke volume index reflects, in part, decreased left ventricular volumes in the short daily dialysis group but may also be indicative of reduced peripheral vascular resistance. Thus, our results suggest that short daily dialysis may lead to reductions in LVH in large part through significant decreases in volume and pressure loading.
However, the correlation of reduction in serum phosphorus and reduction in LVMI seen in our study (Figure 2) provides an additional potential mechanism for beneficial effects of short daily hemodialysis on LVH that are independent of extracellular fluid volume and BP effects. The effects of hyperphosphatemia on LVH are likely multifactorial, although there is a body of evidence suggesting a link between hyperphosphatemia and decreased vascular compliance, which may, in turn, lead to increased afterload and LVH. Recent work has shown that vascular calcification, at the cellular level, is an active process that can be induced by hyperphosphatemia (42). Hyperphosphatemia in cell culture can induce phenotypic changes in vascular smooth muscle cells, upregulating genes associated with bone formation (osteocalcin, osteopontin, and Runx2) and leading to apatite deposition in the matrix surrounding the cells (42–44). Elevated extracellular phosphate levels leads to increased cellular uptake of phosphate via pit-1, a type III sodium-phosphate co-transporter (42). The ensuing elevated intracellular phosphate levels induce the cellular transformation that ultimately leads to the release of pro-calcifying factors (including calcium binding proteins and alkaline phosphatase) (43). These findings show that vascular calcification induced by hyperphosphatemia is a regulated process with similarities to bone mineralization and not a passive phenomenon. A recent animal study extended these in vitro findings using a model of rats that underwent 5/6 nephrectomy and parathyroidectomy with PTH replacement, in which elevated phosphorus in the absence of hyperparathyroidism led to cardiac hypertrophy without development of overt vascular calcification (35). Finally, recent work has shown the applicability of these findings in humans. Hyperphosphatemia has been associated with increased carotid artery medial thickness in ESRD patients, suggesting that vascular compliance may be affected by hyperphosphatemia (45). Thus, a picture is emerging that hyperphosphatemia, by inducing vascular calcification, leads to decreased vascular compliance, which subsequently contributes to LVH. Our study is the first to demonstrate that control of phosphorus is associated with a reduction in LVMI, likely through increases in vascular compliance, providing a potential novel mechanism for the known association of hyperphosphatemia with increased cardiac mortality in hemodialysis patients.
The second novel finding is that inflammatory markers were reduced in patients who received short daily hemodialysis. Chronic inflammation is linked to poor cardiovascular outcomes (7,8,17) in patients who receive chronic hemodialysis. Removal of infected, clotted AV grafts (14–16) and removal of failed kidney allografts (46) are two measures that can ameliorate inflammation in selected patients; however, in the general hemodialysis population, there are few effective therapeutic options. Statins seem to have favorable effects on inflammatory markers (47), but this has not been demonstrated among maintenance hemodialysis patients to date. The potential to increase levels of inflammation is a theoretical disadvantage of short daily hemodialysis, as increased exposure to the extracorporeal circuit can enhance inflammation (48). However, release of inflammatory cytokines is attenuated with the use of more biocompatible membranes (18), and previous investigators have shown that CRP levels do not necessarily increase in patients who receive nocturnal home hemodialysis (27). Our study shows, for the first time, that short daily hemodialysis using high-flux, biocompatible membranes is associated with significant decreases in CRP levels. In addition, ERI decreased and serum albumin increased in the short daily hemodialysis group, which is consistent with improvement in levels of chronic inflammation.
It is interesting that at the end of the 12-mo follow-up, we found a lower point prevalence of moderate to severe peripheral vascular calcification in patients who received short daily hemodialysis compared with conventional hemodialysis. Control of phosphorus level and calcium × phosphorus product in the short daily hemodialysis group and reduced use of calcium-containing phosphate binders, which have been associated with accelerated vascular calcification (49), are potential factors that may have mediated less vascular calcification in the short daily hemodialysis group. A case report of symptomatic improvement of peripheral vascular disease with nocturnal home hemodialysis has been reported recently (50). Thus, short daily hemodialysis, like nocturnal home hemodialysis, may prove to be an adjunctive therapy in patients with ESRD complicated by peripheral vascular disease, although definitive randomized trials are needed. Despite increased paricalcitol doses in the short daily hemodialysis group during the study period, less peripheral vascular calcification was seen at the end of follow-up. This raises the possibility that phosphorus and calcium × phosphorus product may be more important factors than paricalcitol dose for vascular calcification. Although lack of baseline data on severity of peripheral vascular calcification argues for a cautious interpretation of our findings, it is unlikely that short daily hemodialysis would worsen the progression of vascular calcification compared with conventional hemodialysis.
The strength of our study is the enrollment of a larger number of high-risk patients compared with previous studies of daily dialysis and the use of a well-matched concurrent control group. The major weakness of this study, common to all existing investigations of frequent dialysis regimens, is the nonrandomized, open-label study design. Thus, we cannot rule out the possibility of residual confounding, although we adjusted carefully for known factors that affect outcomes in this population, and the baseline risk profile was more adverse among patients in the short daily hemodialysis group. Unlike previous studies, Hispanics and individuals with diabetes were overrepresented in the study sample, whereas there was relatively modest representation of black and non-Hispanic white individuals as compared with the general ESRD population in the United States. Thus, our findings may not be completely generalizable to all patients with ESRD or in other health care settings. Finally, differences in the distribution of prevalent versus incident dialysis patients in the two treatment groups raises the possibility of survivor bias, which precludes definitive conclusions about the changes and implications of phosphorus and CRP levels associated with receipt of short daily hemodialysis.
In conclusion, short daily hemodialysis is associated with improved fluid volume management and reductions in LVMI and inflammatory markers. In addition, improved phosphorus control, independent of correction of anemia and BP or fluid volume control, was associated with a reduction in LVMI. Our findings support the need for larger randomized trials with longer follow-up to determine whether short daily hemodialysis can decrease morbidity and mortality in patients who have ESRD and require maintenance hemodialysis.
We thank the Board of Managers of University Health System of Bexar County, TX, for financial support; Luis Vera, J.D., for advocacy and support of this study; and patients and staff who made this study possible. We also thank Dr. Meeney Dhir for critical review of the manuscript.
Published online ahead of print. Publication date available at www.jasn.org.
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