1Department of Dialysis and Nephrology, Vicenza, Italy and 2Fresenius Medical Care, Bad Homburg, Germany
Correspondence and offprint requests to: Mariano Feriani, Ospedale Umberto I, Divisione Nefrologia and Dialisi, Via Circonvallazione, 50, 30174 Mestre, Italy. Email: mferiani{at}goldnet.it
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Abstract |
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Methods. Two concentrations of bicarbonate in PDF were compared in this study (34 and 39 mmol/l). Eligible patients underwent a pre-study phase of 12 weeks to determine serum bicarbonate every six weeks. Sixty-one patients entered the stratification phase. Acidotic patients (serum venous bicarbonate <25.3 mmol/l) were allocated to the high bicarbonate solution, patients in the normal serum bicarbonate range or alkalotic patients (serum venous bicarbonate >25.3 mmol/l) to the low bicarbonate solution. Patients were followed up for 24 weeks, in which study visits were performed every 6 weeks to assess acidbase status, peritoneal and renal function, and to calculate protein nitrogen appearance rate (PNA).
Results. Patients with acidosis at baseline had higher body weight, body surface area, blood urea nitrogen, serum creatinine and PNA than patients with bicarbonate within the normal range or with alkalosis. They significantly improved their serum bicarbonate (23.45 ± 2.5 vs 25.7 ± 2.8 mmol/l, baseline vs week 24; P < 0.01), whereas patients treated with the low bicarbonate PDF maintained their serum venous bicarbonate over the 24 week study period (27.77 ± 2.9 vs 27.06 ± 2.1 mmol/l, baseline vs week 24; P = NS). Analysing both study groups together, at baseline, 66% of the patients presented with mild to moderate acidosis, this figure at the end of the study was 23.4%. PNA did not change in the two groups; however, in the subgroup of patients (N = 23) in whom the 39 mmol/l PDF was effective in correcting metabolic acidosis, a decrease in PNA was observed.
Conclusions. The study demonstrated that the individualized application of low and high bicarbonate PD PDFs allows one to achieve normal acidbase status in a large percentage of CAPD patients with potential benefits to nutritional status.
Keywords: acidbase status; bicarbonate; CAPD; dialysis adequacy; nutritional status
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Introduction |
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In clinical practice, normal values of serum bicarbonate are achieved only in 25% of CAPD patients by using a PDF containing 35 mmol/l lactate [1], while the use of a PDF containing 40 mmol/l lactate increases this percentage to
40%, but also increases the number of patients with an alkalotic serum bicarbonate concentration [7].
The large inter-patient variability is due to a number of individual factors influencing the base requirements in different patients [1]. Among them, protein intake and catabolism, distribution space for bicarbonate, dialytic fluid removal and peritoneal membrane permeability are probably the most important.
Even though a daily supplement of oral alkalinizing salts could increase serum bicarbonate in dialysed patients [8], the intestinal absorption of calcium-containing phosphate binders (calcium carbonate and acetate) is variable and the alkalinizing effect moderate [6], and sodium bicarbonate exposes patients further to the risk of sodium and fluid retention. Moreover, patient compliance is often not optimal. Therefore, peritoneal dialysis fluids (PDFs) based on bicarbonate, the absorption of which is dependent on the individual serum bicarbonate concentration, are ideal.
Different bicarbonate-based PDFs for CAPD have recently been introduced [9,10]. We recently reported the results of a multicentre randomized study in which a conventional PDF containing 35 mmol/l lactate was compared with a new PDF containing 34 mmol/l bicarbonate [11]. Besides high tolerability reflected by the reduction of infusion pain and discomfort, an unexpected result was a small, but significant, increase in serum bicarbonate. Despite this improvement, a substantial number of patients still had a serum bicarbonate concentration lower than normal.
In a subsequent pilot study [12] we tested a PDF with a higher bicarbonate concentration (39 mmol/l) in a few patients. As expected, serum bicarbonate rose in all patients, but in those patients with normal acidbase status at the baseline, a mild metabolic alkalosis developed.
None of these studies addressed the use of an individual buffer concentration. Therefore, the present study was designed to assess the possibility to normalize the serum bicarbonate level in CAPD patients by individualized application of PDFs with two different bicarbonate concentrations.
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Materials and methods |
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Sixteen European study centres participated. Patients on regular CAPD treatment with a PDF containing 35 mmol/l lactate entered a pre-phase of 12 weeks in which they maintained their dialysis regimen and were assessed at weeks -12, -6 and 0 for acidbase status and other parameters. Depending on the mean of the venous bicarbonate values recorded during the run-in phase at weeks -12 and -6, they were stratified to be treated either with low (34 mmol/l) or high (39 mmol/l) bicarbonate PDF. Patients were classified as normal or alkalotic and allocated to the low bicarbonate PDF if the venous bicarbonate value was above 25.3 mmol/l (normal range for venous bicarbonate from 25.3 to 28.7 mmol/l [13]). If the mean venous bicarbonate value was below 25.3 mmol/l, patients were classified as acidotic and treated with the high bicarbonate (39 mmol/l) PDF.
If a patient in the low bicarbonate group became acidotic (venous bicarbonate lower than 25.3 mmol/l) he/she was switched to the high bicarbonate group, whereas, in the case of metabolic alkalosis in the high bicarbonate group (venous bicarbonate higher than 28.7 mmol/l), the patient was switched to the low bicarbonate group. These changes were based on six-weekly measurements which had to be confirmed 1 week later, prior to a switch.
Patients
Eligible patients were 1880 years old and on CAPD for at least 3 months. All patients had to be free of peritonitis for at least 4 weeks prior to the study. An uncomplicated peritonitis episode during the study period was no reason for withdrawal. Patients with pulmonary dysfunction, malignancies, weekly total Kt/V <1.7 and patients on oral bicarbonate supplementation were excluded from the study.
Approval was obtained from ethics committees at each centre and written informed consent was given by every patient. Patients could withdraw from the study at any time.
Study medication
The CAPD standard prescription (three to five 1500 or 2000 ml bag exchanges per day with more than 90% of the patients in each group receiving four times 2000 ml solutions per day, with an average glucose concentration of 1.83 ± 0.45 and 1.79 ± 0.44% in the 34 and 39 mmol/l bicarbonate PDF groups, respectively) remained unchanged during the study as was the oral dose of calcium carbonate. Three different PDFs manufactured by Fresenius Medical Care (Bad Homburg, Germany) were used during the study. The composition of the employed PDFs is reported in Table 1.
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Study parameters
From weeks -12 to 24, seven visits were performed (every 6 weeks). At each visit a physical examination was performed including measurements of body weight, blood pressure and heart rate, assessment of complications and compliance to dialysis and therapy prescriptions. Blood samples for sodium, potassium, chloride, calcium (total and ionized), magnesium, phosphate, urea and creatinine were taken at each visit. Venous acidbase status was also evaluated every 6 weeks, whereas the evaluation of arterial acidbase status was suggested but was not mandatory.
Standard biochemistry (AST, ALT, gGT, aP, LDH, CPK, bilirubin, albumin, total protein, glucose, cholesterol and triglycerides, lactate, PTH) and haematology (haemoglobin, haematocrit, leukocytes, platelets, differential blood count) were evaluated every 12 weeks.
Assessment of residual renal function [glomerular filtration rate (GFR): mean of residual renal creatinine clearance and urea clearance] and a peritoneal function test [14] were performed at weeks -12, -6, baseline, weeks 12 and 24. From these data, the weekly Kpt/V (peritoneal urea clearance multiplied by 7 days and normalized to body water), the weekly Kprt/V (the sum of peritoneal and renal urea clearance multiplied by 7 days and normalized to body water), the weekly creatinine clearance [the sum of peritoneal and renal creatinine clearance multiplied by 7 days and normalized to 1.73 m2 body surface area (BSA)], the daily protein catabolic rate (PNA: protein equivalent of nitrogen appearance) and the daily protein catabolic rate normalized to body weight (nPNA: normalized protein equivalent of nitrogen appearance) were calculated according to Gotch and Keen [14]. The BSA was calculated using the DuBois equation. The urea distribution volume (V) was derived from gender and BSA.
Laboratory methods
Biochemical parameters were measured using standard laboratory methods established in each study centre.
Acidbase status was evaluated by measuring pH and pCO2 using a conventional blood gas analyser. Actual bicarbonate concentration was calculated from the HendersonHasselbalch equation.
Statistical analysis
Paired and unpaired t-tests were used for comparing acidbase, peritoneal function parameters and biochemistry. The MannWhitney U-test for non-parametric measures was used for age, duration of CAPD and oral calcium-containing phosphate binders supplementation. Where appropriate, correlation analysis was performed. Data are given as mean ± SD. Where P < 0.05, statistical significance is assumed.
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Results |
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Reasons for drop-out were: peritonitis (5), inadequate ultrafiltration (UF) (2), withdrawal of consent (4), a social problem (admission to a supportive care hospital) (1), transplantation (1) and inadequate dialysis requiring dialysate volumes not available as study bags (2.5 l) (1). Patients with acidosis at baseline tended to be younger and to undergo treatment with CAPD for a shorter period of time, but these findings were not significantly different. Several other baseline parameters are listed in Table 2. Significant differences were found between the groups at baseline for body weight, BSA, blood urea nitrogen (BUN), serum creatinine, Kprt/V and PNA (Table 3). Intake of calcium-containing phosphate binders was not different between the groups (3.3 ± 3.3 g/day for the low bicarbonate solution and 3.4 ± 2.8 g/day for the high bicarbonate solution; P = NS).
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Four patients of the low bicarbonate group and five patients in the high bicarbonate group switched to the respective other group according to the protocol. Patients switching from low to high bicarbonate PDF because of non-normalized serum bicarbonate levels tended to have higher body weight and BSA at month 0 than those maintaining the low buffer solution, whereas patients who switched from high to low bicarbonate-containing solution for increasing serum bicarbonate values tended to have lower body weight, BSA and much lower PNA than those maintaining the high buffer solution (Table 4). Statistical analysis failed to show significant differences (P = 0.079 for PNA) because of the small number of patients who changed the solution.
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Urea nitrogen appearance, peritoneal function parameters and other biochemical parameters
PNA was inversely correlated to serum bicarbonate at baseline. It did not change in the two groups (Table 6). A further analysis demonstrated, however, that PNA significantly decreased in those patients (n = 23) with acidosis at baseline, in whom the high bicarbonate PDF was effective in restoring the normal acidbase status.
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Safety parameters, side effects
No differences within groups and between groups were recorded for any other parameter, e.g. ionized calcium, PTH, phosphate, potassium and albumin. No unexpected side effects were observed during the study.
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Discussion |
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What is still a matter of debate is the desired serum bicarbonate level. In haemodialysis, two randomized studies examining the effect of increasing dialysate bicarbonate concentration on nutritional parameters have resulted in opposite conclusions: Brady and Hasbargen [16] did not find any effect on serum albumin and total lymphocyte count, taken as nutritional markers, in two groups of patients treated with a high and a low bicarbonate concentration despite a significant difference in predialysis arterialized bicarbonate (17.3 ± 3.2 and 20.2 ± 2.9 mmol/l, respectively). In contrast, Williams et al. [15] found in a cross-over study a significant increase in triceps skin-fold thickness associated with an increase in predialysis arterialized total CO2 for the study phase in which the patients were treated with the high bicarbonate dialysate (from 22.5 ± 3.2 to 26.7 ± 3.9 mmol/l and from 22.0 ± 2.6 to 23.3 ± 2.8 mmol/l in the two studied groups). This beneficial effect was then reversed by resuming the low bicarbonate dialysate. The major difference in these two studies were the levels of serum bicarbonate achieved: despite an improvement, the serum bicarbonate concentration of the study by Brady and Hasbargen [16] was far from the normal range (25.2 ± 1.0 mmol/l for arterialized bicarbonate [13]), whereas in the second study [15] a substantial number of patients achieved normal values [26.4 ± 1.0 mmol/l for arterialized total CO2 [13]).
The largest study in CAPD patients was undertaken by Stein et al. [6]. Two hundred new CAPD patients were randomly allocated to receive either a 40 mmol/l lactate-buffered PDF or a 35 mmol/l lactate-buffered CAPD PDF. The target venous bicarbonate in the first group was 30 mmol/l and if this was not achieved an oral supplementation with calcium carbonate and sodium bicarbonate was added. Although the target was not reached in all patients, a normal acidbase status (venous serum bicarbonate 27.2 ± 0.3 mmol mmol/l) (normal range 25.328.7 mmol/l [13]) was achieved. The correction of metabolic acidosis led to greater increases in body weight and mid-arm circumference and decreased morbidity in terms of number of admissions and days in the hospital in the first year of CAPD. These data support the view that the target for the acidbase correction in dialysis patients should be the normal value for the healthy population.
This value is, however, difficult to achieve in the majority of patients treated with renal replacement therapies. In particular, only 25% of CAPD patients treated with the 35 mmol/l lactate-buffered PDF achieve the serum bicarbonate target [1]. These data were confirmed in our study in which 66% of the population presented with lower than normal bicarbonate levels at the start.
Our results have demonstrated that the majority of patients presenting mild or moderate metabolic acidosis can achieve a normal acidbase status by using a 39 mmol/l bicarbonate PDF. In order to avoid excessive alkalosis in patients presenting with normal acidbase status, the application of the 34 mmol/l solution proved to be adequate.
The application of the solution with 39 mmol/l bicarbonate substantially improved venous bicarbonate in patients with acidosis and thus reduced the percentage of acidotic patients (from 65.9 to 23.4% of the overall patient population). The modulation of buffer concentration by using the solution containing lower bicarbonate concentrations allowed us to keep the percentage of alkalosis low in our population (12.7%). This percentage also includes those patients with alkalosis at the baseline and treated with the PDF containing 34 mmol/l bicarbonate.
Kang et al. [17] reported a rate of 30.8% of metabolic alkalosis in 143 patients treated with a conventional 40 mmol/l lactate-buffered PDF. This result is in accordance with our data since the mean BSA of their population was 1.62 m2, even lower than that of our patients treated with the low bicarbonate PDF because of a normal acidbase status.
Tranaeus [10] reported a study on a bicarbonate (25 mmol/l) and lactate (15 mmol/l) PDF in 70 patients with a mean body weight of 71.9 kg, close to the body weight of our population with acidosis. After 6 months, mean venous bicarbonate from 35 available measurements was 28.1 ± 2.6 mmol/l. Unfortunately, the different normal range for bicarbonate used in this study did not allow a comparison with our approach of selecting the appropriate buffer concentration. Nevertheless, in this study, 27.5% of patients presented at least two values of 30 mmol/l or higher of venous bicarbonate.
There are very few data in the literature about the clinical consequences of alkalosis. Alkalosis depresses the central nervous system, increases neuromuscular excitability, causes hypokalaemia, cardiac arrhythmias, enhances digitalis intoxication and increases binding of oxygen to haemoglobin, preventing the release of oxygen to peripheral tissues [18]. These effects were described in acute alkalosis while clinical effects in long-term mild chronic alkalosis are still unknown. Periarticular calcifications were associated with alkalosis in alkalotic patients treated with a 40 mmol/l lactate CAPD PDF [19]. Despite the lack of evidence on the detrimental clinical effects of chronic alkalosis, it still seems prudent to try to avoid it in dialysis patients.
An analysis of our population at baseline was performed to understand which factors affect the stratification, and thereby the need to use a PDF with one or the other bicarbonate concentration. It demonstrated that body weight, BSA and protein nitrogen appearance (PNA) were inversely correlated with serum bicarbonate. This is quite understandable as the dialysis prescription (4 x 2 l exchanges) and consequently the buffer supply by the dialysis fluid, which is a well known factor influencing serum bicarbonate concentrations, was not different during the run-in phase, while the PNA (that represents the sum of protein intake and catabolism) was greater and consequently the metabolic acid production higher in larger patients. Therefore, a larger distribution space for bicarbonate and a greater PNA resulted in a lower serum bicarbonate concentration. In order to improve serum bicarbonate levels in patients with a higher acid production, an increased amount of buffer should be supplied and this could be done by increasing the buffer concentration in the dialysis fluid or by increasing the dialysis volume prescribed. The analysis of further parameters revealed that Kprt/V was significantly lower in the group with acidosis, although in both groups this parameter was substantially higher than that recommended by K-DOQI guidelines [20]. Neither UF nor residual renal function were correlated to serum bicarbonate levels.
An increase of serum bicarbonate by means of an increase of buffer infusion was expected to lead to less protein breakdown and consequently to a decrease in PNA [8]; however, this effect was only recorded in those patients in which an effective correction of acidbase was achieved. Our results are in agreement with the study of Stein et al. [21] performed in 11 CAPD patients in which the intervention was done with an oral alkali supplementation.
Our study demonstrated that, for achieving a normal acidbase status in a large percentage of CAPD patients, buffer infusion with dialysis fluid should be adjusted to the individual patient characteristics. A fluid containing the high bicarbonate concentration should be employed in patients with larger body size and relatively high protein intake, while the solution containing the low bicarbonate concentration is useful in patients with smaller body size and low protein intake, thus avoiding alkalosis. Our study indicated, although indirectly based on changes of PNA, that beneficial effects on nutrition resulting from the correction of metabolic acidosis could only be recorded when the normal range of serum bicarbonate was achieved.
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Acknowledgments |
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Conflict of interest statement. M. Feriani and the other members of the Study Group received an educational grant from Fresenius Medical Care for performing the study. J. Passlick-Deetjen is an employee of Fresenius Medical Care and I. Jaeckle-Meyer has been an employee of Fresenius Medical Care during the course of the study. G. La Greca declared no conflict of interest.
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References |
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