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SERUM BNP CONCENTRATION AND LEFT VENTRICULAR MASS IN CAPD AND AUTOMATED PERITONEAL DIALYSIS PATIENTS

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SERUM BNP CONCENTRATION AND LEFT VENTRICULAR MASS IN

CAPD AND AUTOMATED PERITONEAL DIALYSIS PATIENTS

Nüket Bavbek,

1

Hatice Akay,

2

Mustafa Altay,

2

Ebru Uz,

1

Faruk Turgut,

1

Mehtap E. Uyar,

3

Aydýn Karanfil,

4

Yusuf Selcoki,

4

Ali Akcay,

1

and Murat Duranay

2

Department of Nephrology,

1

Fatih University Medical School; Department of Nephrology,

2

Ankara

Education and Research Hospital; Department of Internal Medicine

3

and Department of

Cardiology,

4

Fatih University Medical School, Ankara, Turkey

Correspondence to: N. Bavbek, Harbiye Mah, Nigde Sokak, 46/2 Dikmen, Ankara, Turkey.

ntbavbek@yahoo.com

Received 2 March 2007; accepted 24 May 2007. ♦

♦♦ ♦

♦ Objective: To compare ultrafiltration under continuous ambulatory peritoneal dialysis (CAPD) and automated PD (APD), disclosing potential effects on serum B-type natri-uretic peptide (BNP) levels and echocardiographic findings. ♦

♦♦ ♦

♦ Patients and Methods: This cross-sectional clinical study included 32 patients on CAPD and 30 patients on APD with-out clinical evidence of heart failure or hemodynamically significant valvular heart disease. Peritoneal equilibration tests, BNP levels, and echocardiographic measurements were performed in each subject. BNP measurements were also performed in 24 healthy control subjects.

♦ ♦♦ ♦

♦ Results: Patients on APD had lower ultrafiltration and higher values of BNP and left ventricular mass index (LVMI) compared with patients on CAPD (respectively: 775 ± 160 vs 850 ± 265 mL, p = 0.01; 253.23 ± 81.64 vs 109.42 ± 25.63 pg/mL, p = 0.001; 185.12 ± 63.50 vs 129.30 ± 40.95 g/m2, p = 0.001). This occurred despite higher mean dialysate glucose concentrations and far more extensive use of icodextrin in the APD group.

♦ ♦♦ ♦

♦ Conclusion: Treatment with APD is associated with higher plasma BNP levels and LVMI compared to CAPD. This may be the result of chronic fluid retention caused by lower ultra-filtration in APD patients.

Perit Dial Int 2007; 27:663–668 www.PDIConnect.com

KEY WORDS: CAPD; APD; ultrafiltration; B-type natri-uretic peptide (BNP); left ventricular mass index.

F

luid removal and prevention of volume overload is the

primary target of dialysis therapy. Peritoneal dialy-sis (PD) has been claimed to provide adequate fluid and sodium removal rates (1) by providing a gentle continu-ous ultrafiltration (UF) (2). However, extracellular vol-ume overload may be relatively frequent in patients

undergoing PD, especially after residual renal function declines (3–7), and appears to portend a significant risk of cardiovascular morbidity and mortality (8–10).

Automated peritoneal dialysis (APD) is an increasingly utilized modality that is often used in preference to con-tinuous ambulatory peritoneal dialysis (CAPD) to improve dialysis adequacy or for lifestyle reasons. However, there is a paucity of information on the compared ability of CAPD and APD to control extracellular volume. Patently low UF and sodium removal rates in patients undergoing APD have been reported (11,12) but the clinical consequences of putative differences in extracellular volume control between CAPD and APD have not been assessed in depth. B-type natriuretic peptide (BNP) is a hormone syn-thesized and released by left ventricular (LV) monocytes, and its generation rate is amplified by heart failure or LV hypertrophy. Several studies have examined the util-ity of BNP for the detection of volume status, systolic dysfunction, or LV hypertrophy in the general popula-tion and in dialysis patients. The signals inducing BNP gene expression, and therefore hormone synthesis, seem to be related to an increased intraventricular pressure or volume (13–15). Left ventricular hypertrophy and cardiovascular mortality are highly represented in dialy-sis patients (16,17) and one of the causes is represented by chronic fluid overload (18).

The aims of the present study were to compare UF in patients undergoing CAPD or APD and to investigate the relationships between serum BNP levels and echocardio-graphic findings and UF under both techniques.

MATERIALS AND METHODS PATIENTS

Peritoneal dialysis programs of the Fatih University School of Medicine Dialysis Unit (23 patients) and the

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exchange of 14 ± 2 hours with 2 L of 2.27% glucose PD4 (Baxter ). Ultrafiltration therapy was maximized in both groups by the dialysis prescription. The main target of pre-scription in both groups was dialysis adequacy: total Kt/V ≥2.0 in CAPD patients and ≥2.1 in APD patients, and total creatinine clearance ≥60 L/week/1.73 m2 in CAPD patients

and 62 L/week/1.73 m2 in APD patients.

Twelve patients in the CAPD group and 10 patients in the APD group were anuric; the patients with residual renal function in the CAPD group had a urine output of 530 ± 146 mL/day, and in the APD group, 554 ± 182 mL/ day (p > 0.05).

LABORATORY MEASUREMENTS

Blood sampling for BNP was performed between 8:00 and 10:00 hours with an empty abdomen, after 20 to 30 minutes of quite resting in a semi-recumbent posi-tion. All samples were taken into chilled EDTA vacuum blood-collection tubes, placed immediately on ice, and centrifuged within 30 minutes at 4°C; the plasma was stored at –80°C until assayed. Blood samples were ana-lyzed using the Triage BNP fluorescence immunoassay (Biosite Diagnostics, San Diego, California, USA). In ad-dition, BNP measurements were performed in 24 healthy subjects (12 women, 12 men; mean age 38.2 years) as an sex- and age-matched reference group.

Serum C-reactive protein levels were measured using a nephelometric assay (Boehringer, Mannheim, Ger-many). Concentrations of urea, creatinine, albumin, cal-cium, and phosphorus were determined using standard procedures.

ECHOCARDIOGRAPHY

Echocardiographic measurements were carried out using an echocardiograph (Acuson Cypress ultrasound system; Acuson, Mountainview, California, USA) accord-ing to the recommendations of the American Society of Echocardiography (20) within 3 hours after blood sam-pling, using a 3.75-MHz transducer. Left ventricular mass was calculated according to the Devereux formula (21) and was divided by body surface area to determine the left ventricular mass index (LVMI), presented in grams per meter squared (22). Left ventricular hypertrophy was defined by a LVMI of >106 g/m2 in women and >114 g/m2

in men (23).

PERITONEAL EQUILIBRATION TEST (PET)

All patients had a PET (using 2.27% glucose) from which their solute transport status and UF capacity were Ankara Research and Training Hospital Dialysis Unit

(74 patients) were screened to identify patients that had been on regular PD treatment for at least 1 year, had good compliance to the technique, had remained in the same PD modality in the last year of therapy, had no clinical evidence of heart failure or hemodynamically significant valvular heart disease, atrial fibrillation, or severe mal-nutrition (decrease of dry body weight ≥10% over the previous 3 months, body mass index ≤18 kg/m2, serum

albumin ≤3.2 g/dL, and serum cholesterol ≤150 mg/dL), and did not have a history of peritonitis for at least 3 months. A total of 62 patients (64% of the whole PD patient population: 34 males and 28 females, 32 on CAPD and 30 on APD) were eligible for the study. The remain-ing 45 patients were excluded because of the presence of circulatory congestion (18 patients: 11 on APD and 7 on CAPD) or major infections (16 patients: 10 on CAPD and 6 on APD), or because they were hospitalized for in-tercurrent illnesses (6 patients: 3 on CAPD and 3 on APD), or were unwilling to participate (4 patients: 3 on CAPD and 1 on APD), or had poor compliance with the tech-nique of APD (1 patient on APD).

Automated PD was indicated in patients that preferred home dialysis at night and had significant residual renal function. Patients on APD did not differ according to their peritoneal transport properties. The mass transfer area coefficient of creatinine measured at baseline was 10.9 ± 0.9 mL/minute/1.73 m2 in the APD group and 10.6 ±

0.6 mL/minute/1.73 m2 in the CAPD group (p > 0.05).

Patients that had been treated with CAPD and were switched to APD were not included in the study if the treatment period with APD was less than 1 year. Heart failure was defined as ejection fraction of <35% and dys-pnea associated with two of the following conditions: raised jugular pressure, bibasilar crackles, pulmonary venous hypertension, or interstitial edema on chest x ray, requiring hospitalization or extra UF (19). All par-ticipants were in sinus rhythm at the time of the study. The main demographic and clinical characteristics of the patients included in the study are detailed in Table 1.

Blood pressure was measured 3 times at 5-minute in-tervals in a quiet room, where the patients rested in a su-pine position for at least 15 minutes, using a standard mercury sphygmomanometer and cuffs adapted to arm cir-cumference. Systolic blood pressure was taken as the point of appearance of Korotkoff sounds, and diastolic blood pressure as the point of disappearance of sounds. Blood pressure was defined as the average of 3 measurements.

Patients on CAPD were receiving four exchanges per day using standard dialysis bags (6 – 8 L/day). Standard prescription for APD (HomeChoice Pro; Baxter Healthcare, Deerfield, Illinois, USA) patients included a long day dwell

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determined as described previously (24). The assessment involved the patient collecting each dialysate drain for a 24-hour period, followed the next day by a standardized PET. In CAPD patients, all the exchanges were brought to the hospital and analyzed separately, the net UF being corrected for the overfill of dialysis bags, which bypasses the peritoneal cavity as part of the flush-before-fill pro-cedure but is collected in the drainage bag. For APD pa-tients, long day dwells were treated in a similar fashion, except that there was no overfill flush volumeand the overnight exchanges were collected into a single drain-age bag. Net overnight UF was determined from the APD device and divided by the number of exchanges.

STUDY ETHICS

The study was approved by the Ethics Committee and was conducted in accordance with the ethics principles described by the Declaration of Helsinki. Written in-formed consent was obtained from all participants. STATISTICAL ANALYSIS

All statistical analyses were performed using the SPSS program, version 11.5 (SPSS Inc., Chicago, Illinois, USA). Parameters are given as mean ± standard deviation, with

a p value <0.05 indicating significance. Within- and be-tween-group differences were analyzed by Student’s paired and unpaired t-tests. Correlations were calculated using the Pearson correlation.

RESULTS

There were no significant differences between CAPD and APD patients with respect to age, gender, dialysis duration, body weight, body mass index, C-reactive pro-tein, systolic and diastolic blood pressures, biochemical parameters, or underlying disease (p > 0.05). Demo-graphic and laboratory characteristics of all patients are shown in Table 1. Mean dialysate glucose concentration was significantly higher in APD patients than in CAPD patients (p = 0.015). Also, icodextrin use for long dwells was more common in the APD group than in CAPD and was also statistically significant (p = 0.008) (Table 1).

Plasma BNP levels were markedly higher in APD pa-tients than in CAPD papa-tients: 253.23 ± 81.64 vs 109.42 ± 25.63 pg/mL, p = 0.001 (Table 2). They were also higher than healthy controls (28.5 ± 7.42 pg/mL, p = 0.001). No significant correlation was found between plasma BNP levels and clinical parameters such as duration of PD, systolic and diastolic blood pressures, or serum urea, creatinine, calcium, and phosphorus levels.

TABLE 1

Demographic and Laboratory Characteristics of the Patients

CAPD (n=32) APD (n=30) p Value

Age (years) 32.39±12.47 34.75±18.21 >0.05

Sex (males/females) 19/13 15/15 >0.05

Duration of dialysis (months) 28.44±12.71 24.86±15.47 >0.05

Body mass index (kg/m2) 27.63±8.41 28.46±10.77 >0.05

Systolic BP (mmHg) 124.00±22.94 120.33±26.12 >0.05 Diastolic BP (mmHg) 80.00±8.91 75.56±13.38 >0.05 Underlying disease (n) >0.05 Diabetic nephropathy 12 10 Glomerulonephritis 6 7 Hypertensive nephropathy 5 6

Adult polycystic disease 5 4

Interstitial nephritis 1 1 Other/unknown 3 2 C-reactive protein (mg/L) 8.62±1.25 6.78±2.46 >0.05 Albumin (g/dL) 3.88±0.46 3.69±0.60 >0.05 Calcium (mg/dL) 8.80±0.66 9.19±0.80 >0.05 Phosphorus (mg/dL) 5.35±1.43 5.62±1.10 >0.05 Parathormone (pg/mL) 257.98±58.12 301.08±47.94 >0.05

Mean dialysate glucose (g/day) 116.84±35.92 137.84±37.20 0.015

Icodextrin for long dwell (% of patients) 32.8 58.6 0.008

BP = blood pressure; CAPD = continuous ambulatory peritoneal dialysis; APD = automated peritoneal dialysis. Values are numbers or mean±SD.

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Doppler echocardiographic indices and adequacy pa-rameters are shown in Table 2. M-mode echocardiography revealed an increased LVMI in both CAPD and APD patients and it was significantly higher in APD patients: 129.30 ± 40.95 vs 185.12 ± 63.50 g/m2 respectively, p = 0.001. Also,

interventricular septum end diastolic diameter and LV posterior wall end diastolic diameter were significantly higher in APD patients than in CAPD patients: 7.47 ± 1.41 and 7.41 ± 1.35 mm/m2 in APD patients versus 6.00 ± 0.88

and 6.18 ± 0.89 mm/m2 in CAPD patients respectively (p =

0.005 and p = 0.01 respectively).

There was a positive correlation between plasma BNP levels and LVMI (r = 0.57, p = 0.002). On the other hand, no correlation was found between plasma BNP levels and other echocardiographic parameters. Daily UF was sig-nificantly lower in APD patients than in CAPD patients (p = 0.01) (Table 2).

Twelve of the CAPD patients (37.5%) were on hyper-tensive treatment: 6 on monotherapy with angiotensin-converting enzyme inhibitors, 2 on monotherapy with calcium-channel blockers, 2 on beta-blockers, and 2 on double or triple therapy with various combinations of these drugs. Twenty of the APD patients (66.7%) were on hypertensive treatment: 4 on monotherapy with an-giotensin-converting enzyme inhibitors, 6 on mono-therapy with calcium-channel blockers, and 10 on double or triple therapy with various combinations of these drugs. Antihypertensive drug use was more common in APD patients (p < 0.05).

DISCUSSION

Our results show consistently lower UF and higher BNP and LVMI values in patients on APD compared with

pa-tients on CAPD. This occurred despite higher mean di-alysate glucose concentrations and far more extensive use of icodextrin in the APD group. Also, interventricu-lar septum end diastolic diameter and LV posterior wall end diastolic diameter were higher in APD patients than in CAPD patients. Poor UF on APD may have caused an overhydration status, resulting in LV hypertrophy and elevated serum BNP levels.

There is no previously reported study specifically com-paring BNP and echocardiographic findings under both PD modalities in the clinical setting. At least three stud-ies have yielded results partly consistent with the present report, in which standard APD schedules have been reported to be associated with poor UF (11,12,25). On the contrary, other studies not specifically address-ing this question did not detect such differences (26,27).

There are several possible explanations for the differ-ences found in our study. First, standard APD regimens do not favor maximal UF and Na removal (28). Second, the bulk of therapy in APD is delivered during the night session, but volume load usually appears during the day-time, which may have contributed to overhydration sta-tus in APD. Moreover, short dwell times result in Na sieving, further reducing the ability to remove this cat-ion (29). Finally, recumbency may increase peritoneal solute transport (30), which may be associated with a reduced capacity for UF. On the other hand, the daytime dwell usually lasts 14 – 16 hours, which may also have a negative impact on UF. These limitations can be partially offset by prescribing high dialysate glucose concentra-tions, adding supplementary daytime exchanges (12), or introducing icodextrin for the long dwell (31), but these measures are potentially harmful to the peritoneal TABLE 2

Doppler Echocardiographic Indices, B-Type Natriuretic Peptide (BNP) Levels, and Adequacy Parameters

CAPD APD p Value

Ejection fraction (%) 62.89±9.07 64.67±6.15 >0.05 LVMI (g/m2) 129.30±40.95 185.12±63.50 0.001 IVSTD (mm/m2) 6.00±0.88 7.47±1.41 0.005 LVPWD (mm/m2) 6.18±0.89 7.41±1.35 0.01 LVIDD (mm/m2) 25.94±2.65 28.65±1.94 >0.05 LVISD (mm/m2) 18.24±2.82 18.94±2.76 >0.05 BNP (pg/mL) 109.42±25.63 253.23±81.64 0.001 Total Kt/V 2.47±1.24 2.33±0.91 >0.05

Total creatinine clearance (L/week/1.73 m2) 71.44±6.43 74.94±16.13 >0.05

Daily UF (mL) 850±265 775±160 0.01

LVMI = left ventricular mass index; IVSTD = interventricular septum end diastolic diameter; LVPWD = LV posterior wall end diastolic diameter; LVIDD = LV internal end diastolic diameter; LVISD = LV internal end systolic diameter; UF = ultrafiltration; CAPD = con-tinuous ambulatory peritoneal dialysis; APD = automated peritoneal dialysis.

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membrane, increase the cost of therapy, and can be cum-bersome for many patients.

The UF disadvantage of APD may also be a response to the mechanics of the therapy: The recumbent position may hinder correct drainage of dialysate in many pa-tients. Current PD cyclers are usually programmed to limit drainage times as much as possible, with the aim of maxi-mizing dwell times. In other words, preference is given to a regular and timely sequence of exchanges rather than to a complete emptying of the peritoneal cavity at the end of each exchange. This policy helps to optimize adequacy but may negatively affect final UF, even if the last drainage is allowed to be complete.

Several studies have reported on assaying for BNP in subjects including hemodialysis and PD patients. An in-crease in plasma BNP levels in dialysis patients (32,33) has been documented, and a correlation with LVMI has been observed. High plasma BNP levels have been re-ported in patients with reduced LV function but without clinical evidence of congestive heart failure (34,35). Two recent reports concluded that plasma BNP levels were closely associated with the amount of extracellular water and the overhydration status in hemodialysis patients (34,36). On the other hand, Lee et al. reported that there was no link between extracellular water and serum N-terminal pro-BNP levels. In the same study, N-termi-nal pro-BNP levels were reported to be linked to LVMI and LV ejection fraction in CAPD patients (37). These results indicate that the main secretory stimulus for BNP is stretching of cardiomyocytes caused by volume overload. We believe these observations support our contention.

We observed that APD patients were more frequently using antihypertensive agents than were CAPD patients. This finding may be relevant because poorly controlled, or difficult to control, hypertension is an indirect marker of extracellular volume overload (6,7,38) and is increas-ingly recognized as a predictor of cardiovascular mor-bidity and mortality in patients on PD (9,39).

The limiting factors of the present study are repre-sented by the low number of patients enrolled and the type of the study design. There could be unidentified baseline differences between the two populations that could also, in theory, explain our results, so it would be better to address this issue in a randomized controlled trial with a larger population, with interventional de-signs, to compare the role of fluid overload in left ventricle synthesis of natriuretic peptides and cardio-vascular outcomes in these two PD schedules.

In conclusion, our study appears to provide evidence that plasma BNP levels and LVMI are higher in APD pa-tients than in CAPD papa-tients, which may be the result of chronic fluid retention caused by lower ultrafiltration.

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