Background
Left atrial (LA) volume index (LAVI) has been considered a stable indicator of diastolic dysfunction and an independent predictor of mortality in patients with end-stage renal disease. To date, however, little is known about the relationship between LA enlargement and the changes in residual renal function (RRF).
Methods
This study was undertaken to investigate the association between LA enlargement and the decline in RRF in 121 incident peritoneal dialysis patients. Within 2 months after the initiation of peritoneal dialysis, LA enlargement was determined by echocardiography and RRF by 24-hour urine collection. Subsequently, RRF was measured every 6 months.
Results
The rates of decline in RRF were significantly greater in patients with LA enlargement (LAVI > 32 mL/m 2 ) compared with those without LA enlargement (−0.17 ± 0.18 vs −0.07 ± 0.16 mL/min/month/1.73 m 2 , P = .002). In a linear mixed model, there was a significant difference in the rates of RRF decline over time between patients with and without LA enlargement ( P < .001). Pearson’s correlation analysis revealed that there were significant inverse correlations between the rates of the decline in RRF and LAVI ( r = −0.22, P = .018). In multiple linear regression analysis adjusted for other risk factors, LAVI was found to be an independent determinant of the rates of decline in RRF (β = −0.026, P = .018).
Conclusions
This study shows that a higher LAVI is independently associated with a more rapid decline in RRF in patients with end-stage renal disease on peritoneal dialysis.
Echocardiography is a well-established technique to estimate the risk for cardiovascular disease and to guide treatment in patients with end-stage renal disease (ESRD). In early studies, left ventricular (LV) mass index, LV ejection fraction (LVEF), and LV chamber volume provided valuable information in these patients. Recently, however, several studies have revealed that left atrial (LA) volume index (LAVI) is also an independent predictor of mortality in patients with ESRD.
The left atrium acts as a contractile pump, as a reservoir that collects pulmonary venous return, and as a conduit for the passage of stored blood from the left atrium to the left ventricle during early ventricular diastole. LA size increases in response to two main pathophysiologic conditions: volume and pressure overload. LA volume overload can result from mitral regurgitation, high cardiac output, left-to-right shunts, or arteriovenous fistulas, while LA pressure overload can ensue from mitral stenosis or increased LV filling pressures secondary to systolic or diastolic dysfunction. In patients on peritoneal dialysis (PD), LA enlargement is commonly observed because of chronic volume overload and increased afterload secondary to LV hypertrophy (LVH). On the other hand, residual renal function (RRF) has been recognized as a significant predictor of morbidity and mortality in patients with ESRD on dialysis. Therefore, determining the risk factors for the decline in RRF has become an important research priority. To date, several risk factors, such as male gender, diabetes, poorly controlled hypertension, and heavy proteinuria, have been demonstrated to be associated with a rapid decline in RRF.
Although some studies have found that the loss of RRF contributes to cardiac hypertrophy and dilatation, whether the decline in RRF is affected by cardiac dysfunction in patients with ESRD has been largely unexplored. Therefore, we conducted this prospective observational study to investigate the effect of cardiac dysfunction on the decline in RRF in patients with ESRD undergoing PD. The relationship between the rates of decline in RRF and LAVI was a particular focus of this study.
Methods
Patients
For this prospective, observational study, all consecutive patients with ESRD who started PD in the Yonsei University Health System between January 2006 and December 2009 were initially considered to be included. We excluded 31 patients who did not perform serial urea kinetic studies including measurement of RRF, 11 patients who had residual urine volume < 100 mL/day at the time of PD initiation, 15 patients who did not undergo echocardiography because of noncompliance or other personal reasons, and 11 patients in whom echocardiography was performed before PD initiation. Of the remaining 157 patients, 36 patients were further excluded for the following reasons: PD duration < 3 months ( n = 5), age < 18 years ( n = 2) or > 75 years ( n = 10), history of hemodialysis or kidney transplantation before PD ( n = 3), severe systolic dysfunction (LVEF < 30%; n = 7), severe mitral stenosis or regurgitation ( n = 3), underlying malignancy ( n = 3), decompensated liver cirrhosis ( n = 2), and current immunosuppressive therapy due to systemic lupus erythematosus ( n = 1). Thus, a total of 121 patients were included in the final analysis.
Data Collection
Demographic and clinical data at the time of PD initiation, including age, gender, and comorbidities, were recorded. The results of the following laboratory tests performed at the same time were also collected: hemoglobin, serum albumin, total cholesterol, uric acid, and high-sensitivity C-reactive protein levels and urinary protein-to-creatinine ratio. A peritoneal equilibrium test was conducted to determine peritoneal transport characteristics, and dialysis adequacy and RRF were measured within 2 months of beginning PD and every 6 months thereafter. Peritoneal transport characteristics were assessed using equilibration ratios between dialysate and plasma creatinine, which were determined by a standardized peritoneal equilibration test using 2 L 4.25% dextrose dwell with dialysate samples taken at 0, 2, and 4 hours and a plasma sample at 2 hours. According to their 4-hour dialysate-to-plasma creatinine ratios, patients were categorized as one of the following four peritoneal transport characteristics: high (above +1 SD from the mean), high average (between the mean and +1 SD), low average (between the mean and −1 SD), or low (below −1 SD from the mean). Drained whole dialysate and 24-hour urine (when RRF was present) were collected within 1 day before the peritoneal equilibration test. Creatinine and urea nitrogen were measured in blood, urine, and drained dialysate. RRF is generally determined by estimated glomerular filtration rates using the creatinine-based Modification of Diet in Renal Disease equation or by creatinine clearance using 24-hour urine. However, in patients with ESRD, RRF is calculated as an average of the 24-hour urine urea and creatinine clearance, because of overestimation by creatinine clearance and underestimation by urea clearance. RRF contributes to not only salt and water removal but also the clearance of small and medium-sized molecular weight uremic toxins. Since medium-sized molecular weight uremic toxins are not readily removed by dialysis, preservation of RRF is an important issue for patients with ESRD to prevent uremic symptoms and signs, including pruritus, inflammation, and mineral bone disease. In addition, RRF is associated with better preserved renal endocrine and metabolic function and superior volume homeostasis. To assess dialysis adequacy, weekly Kt/V urea was calculated as the ratio of 24-hour urinary and drained dialysate urea clearance to total body water. Residual renal Kt was calculated by collecting 24-hour urine and measuring its urea content, which was then divided by the average plasma urea levels for the same 24-hour period to give a clearance term, Kt. Peritoneal Kt was determined in the same way using a 24-hour collection of dialysate effluent. The two Kt terms were combined to give total Kt and were normalized to total body water (V), resulting in Kt/V urea. To obtain weekly Kt/V urea, this value was multiplied by 7. In this study, all patients had weekly Kt/V urea > 1.7, which was the minimal target of dialysis dose for PD patients. In general, minimal target of PD dose can be defined as that dialysis dose above which further increments do not lead to clinically significant improvements in patient outcomes. Such PD dose should also allow the patient to be maintained in reasonably good health without significant uremic symptoms and with patient outcomes at least as good as those associated with well-prescribed hemodialysis.
Echocardiography
Echocardiography was performed in all study subjects with an empty abdomen close to the time of discharge, when the patients were considered to be clinically stable and to be in a euvolemic state, on the basis of the imaging protocol recommended by the American Society of Echocardiography using a Sonos 7500 (Philips Ultrasound, Bothell, WA). LV systolic function was defined by LVEF using a modified biplane Simpson’s method from the apical two-chamber and four-chamber views. LV mass was determined using the method described by Devereux et al. , and the LV mass index was calculated by dividing LV mass by body surface area. LA volume was assessed using the biplane area-length method from the apical two-chamber and four-chamber views and was indexed for body surface area. Measurements were obtained in end-systole from the frame preceding mitral valve opening. According to population-based studies, a value of 32 mL/m 2 was considered as the upper limit of a normal LAVI. Mitral inflow was assessed by Doppler echocardiography from the apical four-chamber view with the Doppler beam aligned parallel to the direction of flow and with a 1-mm to 2-mm sample volume placed between the tips of the mitral leaflets during diastole. The mitral inflow profile was used to measure the peak E-wave velocity and its deceleration time, the peak A-wave velocity, and the isovolumetric relaxation time. Pulsed-wave Doppler tissue imaging of the mitral annulus was also obtained. From the apical four-chamber view, a 1-mm to 2-mm sample volume was placed on the septal mitral annulus, and data were measured from individual beat. Tricuspid regurgitation velocity was recorded from routine right ventricular inflow view using continuous-wave Doppler. Systolic right ventricular pressure was calculated using the modified Bernoulli equation (4 × [tricuspid systolic jet] 2 + 10 mm Hg).
Statistical Analysis
Statistical analysis was performed using SAS version 9.1.3 (SAS Institute Inc., Cary, NC). Continuous variables are expressed as mean ± SD and categorical variables as number (percentage). To compare differences between the two groups, Student’s t test or the χ 2 test was used. The slope of the decline in RRF over time was calculated by linear regression analysis of serial 24-hour urinary urea and creatinine clearances for each patient; the slope is expressed as the regression coefficient (mL/min/month/1.73 m 2 ). Pearson’s correlation analysis was performed to elucidate the relationships between the rates of decline in RRF and other continuous variables. In addition, the difference in the slopes of RRF decline within categorized variables was compared using Student’s t test. Multiple linear regression analysis was used to identify significant determinants of the rates of RRF reduction. Adjusted R 2 values are also provided for multiple linear regression analysis. The changes in RRF over time were compared between patients with and without LA enlargement using a linear mixed model. In our implementation of the mixed model, the intercept and the regression coefficient for the follow-up time were treated as random effects such that each subject had a unique intercept and regression coefficient for the follow-up time. P values < .05 were considered statistically significant.
Results
Baseline Patient Characteristics
The baseline demographic, clinical, and biochemical characteristics are shown in Table 1 . Of the 121 total patients, 46 (38.0%) had LAVI > 32 mL/m 2 and were considered to have LA enlargement. There were no significant differences in the duration of chronic renal failure, comorbidities, medications, biochemical parameters, the proportion of patients on automated PD or using icodextrin, peritoneal membrane permeability, and dialysis adequacy between patients with and without LA enlargement.
| Variable | LAVI ≤ 32 mL/m 2 ( n = 75) | LAVI > 32 mL/m 2 ( n = 46) | P |
|---|---|---|---|
| Age (y) | 48.7 ± 12.9 | 53.2 ± 12.2 | .06 |
| Men | 39 (52.0%) | 32 (69.6%) | .06 |
| Diabetes | 25 (33.3%) | 23 (50.0%) | .07 |
| Hypertension | 64 (85.3%) | 43 (93.5%) | .17 |
| Coronary artery disease | 5 (6.7%) | 8 (17.4%) | .06 |
| NYHA class III or IV | 3 (4.0%) | 4 (8.7%) | .28 |
| Primary kidney disease | .14 | ||
| Diabetes | 24 (32.0%) | 20 (43.5%) | |
| Hypertension | 15 (20.0%) | 8 (17.4%) | |
| Glomerulonephritis | 16 (21.3%) | 3 (6.5%) | |
| Others | 20 (26.7%) | 15 (32.6%) | |
| Duration of chronic renal failure (y) | 11.4 ± 2.4 | 12.2 ± 3.3 | .51 |
| Body mass index (kg/m 2 ) | 23.1 ± 3.0 | 23.0 ± 3.4 | .92 |
| Mean arterial blood pressure (mm Hg) | 96.3 ± 15.2 | 96.2 ± 14.4 | .97 |
| Weekly Kt/V | 2.3 ± 0.5 | 2.3 ± 0.5 | .97 |
| 4-hour dialysate-to-plasma creatinine ratio | 0.7 ± 0.1 | 0.7 ± 0.1 | .74 |
| Urine volume (mL) | 807.6 ± 590.3 | 850.0 ± 469.3 | .68 |
| Hemoglobin (g/dL) | 9.3 ± 1.5 | 8.9 ± 1.4 | .12 |
| Protein (g/dL) | 6.3 ± 0.9 | 6.0 ± 1.0 | .15 |
| Albumin (g/dL) | 3.6 ± 0.6 | 3.5 ± 0.7 | .26 |
| Cholesterol (mg/dL) | 164.1 ± 46.8 | 176.2 ± 58.6 | .24 |
| Uric acid (mg/dL) | 7.7 ± 2.7 | 6.9 ± 2.3 | .09 |
| High-sensitivity CRP (mg/dL) | 1.0 ± 2.3 | 0.9 ± 1.4 | .73 |
| Urinary PCR (mg/mg) | 4.2 ± 4.1 | 5.2 ± 5.1 | .24 |
| Medication use | |||
| ACE inhibitors or ARBs | 54 (72.0%) | 35 (76.1%) | .62 |
| Statins | 23 (30.7%) | 15 (32.6%) | .82 |
| Diuretics | 35 (46.7%) | 27 (58.7%) | .20 |
| Automated peritoneal dialysis | 20 (26.7%) | 18 (39.1%) | .15 |
| Use of icodextrin | 25 (33.3%) | 17 (37.0%) | .68 |
| Peritonitis rate (times/patient-years) | 0.2 ± 0.3 | 0.2 ± 0.3 | .89 |
The differences in echocardiographic parameters between the two groups of patients are presented in Table 2 . Compared with patients with LAVI ≤ 32 mL/m 2 , LV end-diastolic diameter, LV mass index, right ventricular pressure, and the ratio of early mitral inflow velocity to peak mitral annulus velocity (E/E′) were significantly higher in those with LAVI > 32 mL/m 2 . However, there was no significant difference in LV systolic function between the two groups.
| Variable | LAVI ≤ 32 mL/m2 ( n = 75) | LAVI > 32 mL/m2 ( n = 46) | P |
|---|---|---|---|
| LVEF (%) | 62.8 ± 8.4 | 60.5 ± 9.9 | .18 |
| LV end-diastolic diameter (mm) | 50.2 ± 5.4 | 53.6 ± 4.2 | <.001 |
| Interventricular septal thickness (mm) | 10.6 ± 1.8 | 11.7 ± 1.9 | .001 |
| Posterior wall thickness (mm) | 10.3 ± 1.8 | 11.7 ± 1.6 | <.001 |
| LV mass (g) | 198.5 ± 55.6 | 255.4 ± 63.7 | <.001 |
| LV mass index (g/m 2 ) | 118.7 ± 30.4 | 152.9 ± 34.0 | <.001 |
| LA volume (mL) | 40.9 ± 9.7 | 68.2 ± 16.5 | <.001 |
| LA volume index (mL/m 2 ) | 24.5 ± 5.4 | 40.8 ± 8.4 | <.001 |
| Right ventricular systolic pressure (mm Hg) | 27.6 ± 8.4 | 33.2 ± 9.5 | .003 |
| E/E′ ratio | 12.5 ± 4.8 | 17.2 ± 6.8 | <.001 |
| E/A ratio | 0.9 ± 0.3 | 1.0 ± 0.6 | .02 |
Comparison of RRF between Patients with and without LA Enlargement
RRF was measured at least three times in 116 patients (96%), four times in 85 (70%), and five times in 71 patients (59%). As shown in Figure 1 and Table 3 , patients with LA enlargement tended to have higher baseline RRF than those without LA enlargement. At 24 months, however, RRF was significantly lower in patients with LAVI > 32 mL/m 2 . In addition, the overall rates of RRF decline after the start of PD were significantly greater in patients with LA enlargement compared with those without LA enlargement. Moreover, a linear mixed model revealed that there was a significant difference in the rate of RRF decline over time between patients with and those without LA enlargement (coefficient [−1.05, −0.47], P < .001). In contrast, there was no difference in the rates of the decline in estimated glomerular filtration rate, assessed by creatinine-based Modification of Diet in Renal Disease equation, during 2 years before PD initiation between patients with and those without LA enlargement (−0.31 ± 0.15 vs −0.28 ± 0.21 mL/min/month/1.73 m 2 , P = .84).
| Variable | LAVI ≤ 32 mL/m2 ( n = 75) | LAVI > 32 mL/m2 ( n = 46) | P |
|---|---|---|---|
| RRF (mL/min/1.73 m 2 ) | |||
| Baseline | 3.59 ± 3.01 | 4.42 ± 2.35 | .11 |
| 6 mo | 3.40 ± 3.00 | 3.47 ± 2.10 | .92 |
| 12 mo | 2.33 ± 1.91 | 1.92 ± 2.06 | .40 |
| 18 mo | 2.75 ± 4.26 | 1.69 ± 1.70 | .64 |
| 24 mo | 2.74 ± 3.24 | 0.59 ± 1.13 | .014 |
| Slope of decline in RRF (mL/min/month/1.73 m 2 ) | −0.07 ± 0.16 | −0.17 ± 0.18 | .002 |
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