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Calcium kinetics and the long-term effects of lowering dialysate calcium concentration
Kidney international, Vol. 43 (1993), pp. 630—640
Calcium kinetics and the long-term effects of lowering dialysate calcium concentration ANGEL ARGILES, PETER G. KERR, BERNARD CANAUD, JEAN Louis FLAVIER, and CHARLES MI0N LP9008 CNRS and Unit 249 INSERM, Centre de Recherches en Biochimie Macromoleculaire; UDSA. A.i.D.E.R.; and Department of Nephrology, University Hospital "Lapeyronie", Montpellier, France
Calcium kinetics and the long-term effects of lowering dialysate calcium
concentration. The optimal dialysate calcium (Ca) content for hemodialysis has been classically fixed at 1.75 m. However, this dialysate Ca concentration (dCa) with its positive intradialytic Ca balance combined with the use of CaCO3 as a phosphate binder may result in hypercalcemia. To prevent or treat hypercalcemia, a decrease in dCa has been proposed. In the present study both the acute and the long-term effects of lowering dCa were assessed. Additionally, given the results obtained after one year with low dCa the effectiveness of i.v. la vitamin D3 in lowering PTH serum levels in two groups of patients dialyzed with different dCa was also studied. (a) Ca kinetics during hemodialysis (HD) and on line hemodiafiltration (HDF) were studied in a group of nine stable patients who were sequentially treated with 1.75, 1.5 and 1.25 mM dCa. Dialysate was the same but for the dCa which was lowered
75%; P < 0.0313) in both groups within four months of treatment. This study shows that low dCa can be used both in HD and HDF with no associated clinical intolerance. However, the increase in oral Ca intake was not sufficient to prevent the stimulation of PTH secretion observed
with dCa =
1.25
m. Complementary treatment with high doses of
vitamin D derivatives reverses PTH increase both in 1.5 and 1.25 mi dCa treated patients.
Osteoarticular disease is a major concern in hemodialysis
stepwise. Na, K, tCa, ionized Ca (iCa), proteins, phosphate and pH patients. The known pathogenic factors for bone disease in this were measured from blood inlet and outlet and dialysate outlet at the population are multiple and interrelated: hyperparathyroidism, start, one hour, two hours and after the treatments. At the same time aluminum toxicity, osteomalacia and the more recently added weight, blood pressure and heart rate were recorded. The sieving of iCa was significantly different in HDF versus HD (F = 6.73; P < 0.01); dialysis-associated amyloidosis [1]. While the pathogenesis of intravenous infusion of 18 liters of filtered ultrapure dialysate compen- the latter is currently under study, important progress has been sated the Ca loss due to the convective component of HDF, as iCa was achieved in the treatment and prevention of the other three in similar at the blood inlet in HD and HDF in the three dCa tested (F = the last few years. Serum phosphate control can be obtained 2.59; NS). Intradialytic iCa kinetics measured in the blood inlet were significantly different with different dCa (P < 0.001 for 1,75 mM vs. 1.5 without the use of Al-containing phosphate binders and new mm and P < 0.001 for 1.5 m vs. 1.25 mM). A significant increase in vitamin D derivatives with different efficacy, administration post-dialysis iCa was observed with dCa of 1.75 and 1.5 while no techniques and side effects are available or under pre-clinical modification was observed with 1.25 mM dCa. (b) Regarding long-term effects of lowering dCa, seven of the nine patients acutely studied were experimentation [2—4]. However, the new trends in the treatment of hyperparathyroidism generate different problems which followed for a one year period after changing from dCa = 1.5 to dCa = 1.25 ms. A control group of six patients was maintained with dCa = 1.5 for the same period of time and with the same treatment schedule but for dCa. Total Ca, phosphate and alkaline phosphatase were assessed monthly, and phosphate binders and oral vitamin D derivative doses
require modifications of the classical approach to dialysis therapy [5]. One of the limiting factors in the use of high doses of CaCO3 in phosphate control is that of hypercalcemia. To
were adapted accordingly. Intact PTH was determined quarterly. avoid hypercalcemia a reduction in the dialysate Ca content CaCO3 oral intake was more than doubled in the low dCa group. Total (dCa) has been proposed [6]. Ca, phosphate and ALP were similar in both groups over the assessed year. However, a significant increase in PTH was observed after one year treatment with 1.25 mri dCa (94 40 vs. 296 99 pg/ml; P < 0.05) which was not observed in the dCa = 1.5 m control group (92 24 vs. 113 24 pg/mI; NS). (c) For the effects of high-dose i.v. 1 a vitamin D3 on PTH serum levels, six of the patients maintained with dCa = 1.25 mM for one year tolerated the treatment with la vitamin D3. A control group of six patients dialyzed with dCa = 1.5 m and with comparable PTH levels was submitted to identical treatment and follow-up. High dose i.v. Ia vitamin D3 resulted in a similar iPTH reduction (72 and
In the present study we wanted to compare the intrasession Ca kinetics in hemodialysis and our previously-described online hemodiafiltration system [7] using three different dCa concentrations. Besides the acute clinical consequences secondary to the lowering of dCa, long-term results were examined
in a 12 month prospective protocol. Our results show that lowering dCa to 1.25 mri is safe from the point of view of potential hypocalcemia, intradialytic events and blood pressure
control. However, a 2.8-fold increase in oral calcium intake with subsequent normalization of serum Ca levels was not Received for publication September 23, 1991 and in revised form September 30, 1992 Accepted for publication October 1, 1992
© 1993 by the International Society of Nephrology
sufficient to prevent stimulation of PTH secretion, as compared to a control group maintained with 1.5 mrt dCa. High doses of i.v. liz vitamin D3 can be given to both 1.5 and 1.25 ma't dCa treated patients with identical good results in decreasing PTH.
630
631
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
Methods
Long-term effects of using 1.25 m'i dCa
Patients. One patient was transplanted and another was Calcium kinetics and intradialytic studies transferred to another center shortly after the acute study of the Patients. Seven men and two women with stable end-stable 1.25 mri dCa. The long-term effects of lowering the dCa from renal failure gave their consent to participate in the trial. Their 1.5 to 1.25 m were therefore assessed over a one year period mean age was 53.2 4 years old (range: 31 to 72) and they had in the remaining seven patients as well as in a control group of been on kidney replacement therapy for 5.8 1.7 years. Their six patients maintained with 1.5 mri dCa throughout the study.
kidney diseases included chronic glomerulonephritis (3),
Biological parameters. Ca, phosphate and ALP were as-
chronic urinary tract infection (2), Henoch-Schonlein syndrome sessed pre-dialysis monthly. Osteocalcin and intact parathyroid (1), Wegener's disease (1), and undetermined (2). One patient hormone (iPTH) were assessed quarterly by RIA (Incstar Co, Stillwater, Minnesota, USA and Nichols Institute, San Juan was receiving labetalol as the antihypertensive treatment. Capistrano, California, USA). The variability for these tests Kidney replacement techniques. This group of patients was was 3.4% and 5.6% intra- and interassay, respectively. Phosroutinely treated with post-dilutional hemodiafiltration (HDF) phate binders and oral vitamin D derivative doses were adapted for three hours each, three times weekly with A-2008-C Freseto maintain tCa in the higher zone of the normal range (2.5 to 2.7 nius machines and HF8O polysulfone membranes (Fresenius mM) and serum phosphate lower than 1.7 mM.
AG, Bad Homburg, Germany). Blood flow was maintained Blood pressure. Interdialytic systolic and diastolic blood between 350 and 380 mllmin. Sterile, bicarbonate buffered pressures as well as heart rate were monitored for 24 hours with infusate was produced by on-line filtration of ultrapure dialysate a SpaceLabs 90207-31 blood pressure monitor (SpaceLabs Inc., as previously described [7]. Ion contents were: Na 139 mM, K Redmond, Washington, USA) during the use of 1.5 and 1.25 mM 1.5 m, Mg 0.5 mM, Cl 108 mM, HC03 36 m, and the Ca dCa in the study group. There was more than 35 readings per content was decreased from 1.75 to 1.5 and 1.25 mM. A total record. The mean of the one day record was used as the blood convective volume removal of 18 to 20 liters was used with 500 pressure for a given patient and used for analysis. ml/min dialysate flow. Weight was monitored with Gambro weigh beds (Gambro, Lund Sweden), and blood pressure was High dose 1 a(OH) vitamin D3 measured with a Dinamap 8103 (Critikon, Creteil, France). Patients. The seven patients maintained with 1.25 dCa for Dialysis dose was controlled by urea kinetics measurements more than one year, and a control group (also N = 7) with
every month according to Farrel's method [81 as detailed elsewhere [9]; a Kr/V > 1.4 with a PCR> 1 was sought. Simple hemodialysis (HD) without the convective part of HDF but using the same dialysis parameters as above was performed in all patients, with the three dCa concentrations to analyze the differences between HD and HDF.
equivalent PTH serum levels and maintained with 1.5 dCa throughout the study were included in the protocol. Oral 1 a(OH) vitamin D3 was stopped and replaced by i.v. 1 a(OH)
vitamin D3. One patient in each group did not tolerate i.v. la(OH) vitamin D3, and the analysis was performed in the remaining 12 patients separated into two groups according to Parameters. iCa, Na and K were measured with specific dCa concentration (6 patients treated with 1.5 and 6 treated with electrodes (Fresenius EH-F lonometer; the intra-assay and 1.25 mM dCa). interassay variability was <0.1% and <1%, respectively) in Protocol. la(OH) vitamin D3 (Etalpha, Leo Laboratories, blood taken from the arterial and venous sides of the blood Denmark) was administered i.v. at the end of the dialysis circuit, as well as in the dialysate taken from the outlet of the session. The initial dose was 1 .tg (x3/week) which was dialyzer, at the start, one hour, two hours, and at the end of the increased stepwise weekly by I g until a total dose between 6 three-hour dialysis session. Total Ca (tCa) was manually deterto 9 gIweek was given. iCa, tCa, phosphate and ALP were mined by fluorometric measurement of calcein reaction with an assessed weekly. The la(OH) vitamin D3 doses were adapted intra-assay and interassay variability <1%. At the same time according to the predialysis serum iCa levels with the aim of phosphate, total protein and bicarbonate were measured with a maintaining pre-dialysis iCa levels of 2.5 to 2.7 mrvi. Intact PTH Kone autoanalyzer (KONE mc, Finland). and osteocalcin serum levels were assessed monthly. This Protocol of calcium kinetics assessment. The patients were study was conducted for four months at the end of the one year maintained on 1.75 dCa for more than three months, then Ca follow-up with varied dCa.
kinetics were assessed in three consecutive sessions (twice using HDF and a last one with isolated HD). Urea kinetic assessment was performed the consecutive week and the dCa
changed to 1.5 m the week after, with assessment of Ca kinetics in the same way (3 consecutive sessions: 2 HDF and 1 isolated HD) 12 weeks after decreasing dCa to 1.5 mM. Identical
assessment was carried out when the patients were changed from 1.5 to 1.25 mrvi dCa.
Blood pressure and dialysis tolerance. Intradialytic blood
Statistics The Statistical Analysis System package (S.A.S., 1984, Cary, North Carolina, USA) was used. Comparison between two or three groups with several data points each, on a longitudinal basis, was performed with the analysis of the variance using
Fisher's F value. This applied for intrasession kinetics and blood pressure studies (3 different groups with 4 data points
pressure, pulse and weight were recorded before, one hour, two each) and long-term assessment of lowering dCa (2 groups with hours, and at the end of the dialysis session. Intrasession events 12 data points) and subsequent treatment with la(OH) vitamin were recorded during a one month period while the patient was D3 (2 groups with 4 data points). Longitudinal differences treated with the three different dCa concentrations. The results between two given data points were compared with the Student's t-test (normally distributed values) or with Wilcoxon's are expressed as events per 100 dialysis sessions.
632
Argues et a!: Lowering Ca dialysate and hyperparat/zyroidis,n
A Blood inlet
B Blood outlet
1.7
1.5
1.4
0 E
00 a) N
0
00 a)
1.2
0
0
1
I
I
2
3
I 1
Time, hours
C Di-Do
3
hours
1.5
£
1.4.
0 E E
.15
0a) N C
2
o Dialysate outietTime
.20
a)
1.3 1.2
-r
E E
1.4
N C
1.1
0
..D
E E
1.3
0 Ca
.10
1.3.
D
a) N
0 1.2. C
0 .05
.
1.1
0
1
2
3
Time, hours
0
1
2
3
Time, hours
Fig. 1. iCa kinetics during HDF wit/i three different dCa (1.75, 1.5 and 1.25 mM). Arterial (A), venous (B), loss of calcium from dialysate (Di-Do) (C) and dialysate outlet (D) concentrations are plotted (1.75 mai dCa is plotted as filled triangles and dashed line, 1.5 mat dCa as open squares and
dotted line and 1.25 mat dCa as filled circles and solid line).
test for paired data (not Gaussian distributions). Correlations between numeric variables were tested with Pearson's r value and regression analysis was performed when appropriate. The values are given as mean standard error of the mean and a P <0.05 is considered to be statistically significant. Results
Intradialysis studies Ca and phosphate kinetics. The changes in iCa in the course
of HDF for the three dialysate concentrations are shown in
Figure 1. Arterial iCa concentrations were significantly lower as
the dCa was reduced to 1.5 m and to 1.25 mat (F = 114; P < 0.0001). Sequentially analyzing the modifications in the course of dialysis, we observed a significant rise in iCa with dCa of 1.75
and 1.5 m (before vs. after comparison by Student's i-test for
paired data: t = 5.77; P < 0.0004 and t = 4.43; P < 0.003, respectively), while with 1.25 mre dCa, iCa did not change significantly (t = —1.21; NS). The venous blood and dialysate
outlet followed similar trends. The uptake of Ca from the dialysate was different with the three dCa (F 55.6; P <
633
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
A Blood inlet
B Blood outlet
1.7
1.5
1.6
1.4
0
E E
1.3
I
0Va)
______ __e_#._eeaee
1.5
...D
1.4
a)
N C
1.2
0
1.1
1.3 1.2
T
I
0
1
•
I
I
I
I
2
3
0
1
Time, hours
o Dialysate outlet
1.5
.20 a)
0 .15
0
0Va)
0V
i
1.4
E E
E E
N C
3
Time, hours
C Dinlet—Doutlet
a)
I 2
.10
1.3
......
w N C
D
0 1.2
0 .05
1.1
• 0
•
—..-___•___--I
J
I
I
I
I
I
I
1
2
3
0
1
2
3
Time, hours Time, hours Fig. 2. iCa kinetics during HD wit/i three different dCa (1.75, 1.5 and 1.25 mM). Arterial (A), venous (B), loss of calcium from dialysate (Di-Do) (C), and dialysate outlet (D), concentrations are plotted (1.75 mri dCa is plotted as filled triangles and dashed line, 1.5 mss dCa as open squares and dotted line and 1.25 ms dCa as filled circles and solid line).
0.0001); with 1.25 mt dCa it was small (0.06 0.008 mmollliter) and altered little during the course of the dialysis, while with 1.75 and 1.5 mi dCa it was higher and tended to decrease (Fig.
significantly between HD and HDF (F =
2.59;
NS). The
intradialysis kinetics of iCa followed the same trend in HD and HDF except for the sieving of iCa (Fig. 2). The serum phosphate levels (blood inlet and outlet) were not 1C). The sieving of iCa [dialysate outlet (Do)Iblood inlet (Bill was significantly different as the dCa was lowered (F = 1.5; NS) significantly different in HDF when compared to HD alone (F = (Fig. 3). As expected, the reduction in serum phosphate in the 6.73; P <0.01); however, this was compensated in HDF by the course of dialysis was dependent on the initial serum phosphate infusion of 18 liters containing the same Ca concentration of the level (Pearson's, r = 0.83; P < 0.0001). However, this reduction
dialysate. Thus, the iCa at the blood inlet did not differ also correlated with HC03 (r =
0.53;
P < 0.0001), but the
634
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
2). It can be observed that the dialysis dose given to these patients is largely greater than that advised by the NCDS study [10], and it was similar in both groups. Medications. The treatment with CaCO3 and la(OH) vitamin D3 are represented in Figure 5. It can be seen that there was a 2.8-fold increase in the amount of CaCO3 taken while the study progressed after dCa was lowered to 1.25 m. After a one year follow-up, the dose of CaCO3 administered was 12.6 1 and 6.57 1.9 g/day/patient in the groups treated with 1.25 and 1.5 mM dCa, respectively. At the same time Al(OH)3 was com-
2.0
1.5
pletely withdrawn in both groups. Oral 1 a(OH) vitamin D3
o
remained stable during the follow-up period (the extreme values were 1 and 0.86 p,glweek/patient for the study group and 0.96 and 0.67 pg/week/patient for the control group).
1.0
a-
Blood pressure report. None of the patients included in the low dCa group was receiving antihypertensive drugs. The
0.5
24-hour blood pressure records are detailed in Table 3. Systolic blood pressure was unchanged while decreasing dCa from 1.5
m to 1.25 m. By contrast, diastolic blood pressure and heart 0
1
2
3
Time, hours
Fig. 3. Intradialytic modifications of serum phosphate level during HDF. The three different lines correspond to 1.75, 1.5 and 1.25 mM dCa (1.75 msi dCa is plotted as filled triangles and dashed line, 1.5 msi dCa as open squares and dotted line and 1.25 msi dCa as filled circles and solid line).
rate decreased significantly when the patients were switched to
1.25 mrvi dCa (Wilcoxon test P < 0.0469 and P < 0.0313, respectively). Biochemistry. No significant variations were observed in tCa, phosphate and ALP (Fig. 6A, B, and C). tCa was stable during
the one year period (F = 0.9; NS) with values which ranged from 2.38 to 2.53, and was similar in both groups (F = 0.01; NS). Phosphate was also stable (F = 0.49; NS) and similar in both groups (F = 2.78; NS), ranging from 1.5 to 1.89 mmol/liter.
clinical significance of this is uncertain. A weak but significant correlation between the serum phosphate level and iCa sieving (Do/Bi) was observed(r = 0.3 15; P <0.0001). However, it must be pointed out that although the phosphate levels did not alter significantly in the course of the study, the amount of phosphate binders taken by the patients increased (see below), and thus definite conclusions regarding the interrelationship of the serum phosphate and the dCa are difficult to draw. Blood pressure and dialysis tolerance. Figure 4 shows intradialytic changes in systolic and diastolic blood pressure as well
Alkaline phosphatases showed opposite trends in the two groups: while the patients treated with dCa = 1.25 m increased ALP the patients with dCa = 1.5 m decreased their ALP serum levels. However, Wilcoxon's test for paired data was not significant for either group. Similarly, the analysis of the variance did not show statistical differences between the groups (F = 0.21; NS) or over the time of the study period (F = 0.01; NS).
Concerning iPTH values, although initially similar, they
showed a significant increase in the study group over the year (Wilcoxon test; P < 0.047), while the control group remained as heart rate during HDF with the three different dCa. A very stable (Fig. 6D). As a consequence iPTH was statistically decrease in both SBP and DBP during the session was observed different in both groups (F = 4.76; P < 0.036).
which was reversed with fluid restitution at the end of the
dialysis. The heart rate decreased after the start of the session and started to increase from the second hour to compensate for the weight loss. The same patterns were observed with the three different dCa concentrations. DBP significantly decreased when lowering dCa to 1.25 mrvi (F = 4.6; P < 0.01). In contrast, decreasing dCa had no effect on SBP (F = 2.5; NS). The intradialytic events most frequently recorded were hypotension, cramps and headache. As it can be seen in Table 1, the average occurrence of intradialytic events was very low: 10 hypotensive episodes, 2.2 cramps and 1.7 headaches per 100 dialysis sessions, respectively. Although headaches disappeared with dCa = 1.25 m, because of the very low occurrence, the clinical relevance of these variations is not clear.
High dose of i.v. la(OH) vitamin D3 High dose i.v. la(OH) vitamin D3 was effective in lowering iPTH regardless of the dCa. As shown in Figure 7, after four months of treatment, iPTH clearly decreased in both the group maintained with dCa = 1.5 and the group switched to dCa = 1.25 m by 75 9 and 72 9%, respectively. The absolute values were 237 69 pg/liter and 271 150 pg/liter before starting i.v. 1 a(OH) vitamin D3 therapy for the 1.25 dCa and the 1.5 dCa groups, respectively; at the end of the study iPTH was 72 36 and 73 55 pg/liter, respectively. The levels reached with the i.v. 1 a(OH) vitamin D3 treatment were similar to those
observed in the same population 16 months before while they were treated with dCa = 1.5 m. Treatment with i.v. la(OH) vitamin D3 had to be momentarily stopped because of hyperLong-term effects of using 1.25 m dCa phosphatemia on two occasions in each group. No differences were observed in osteocalcin levels either Dialysis dose. The dialysis characteristics and delivered dose as measured by urea kinetic modeling were stable throughout between the groups or after i.v. la(OH) vitamin D3 treatment the follow-up period in both the study and control group (Table (24 3 and 24 5 tg/liter at the start and 24 5 and 28 12
635
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
A
B
160 90
150' E E
140•
a.
a(I)
80'
130 70. 120.
T
•
U
U
U
0
1
2
3
0
Time, hours
1
2
3
Time, hours
90 E a) in ca
80
70
0
1
2
3
Time, hours
pg/liter, respectively, in the study and control groups after 4 months). The evolution of tCa, phosphate and ALP is presented in Table 4. There was a significant increase in tCa in the dCa 1.25 group (P < 0.05). The ALP tended to increase in both 1.25 and dCa = 1.5 mM groups (17.3% and 10% in dCa groups, respectively); however, this increase was not significant.
Fig. 4. Intradialytic changes in SBP, DBP and heart rate with the three different dCa (1.75 m dCa is plotted as filled triangles and dashed line, 1.5 msi dCa as open squares and dotted line and 1.25 mM dCa as filled circles and solid line). Table 1. Intradialysis morbidity during 117 HDF sessions
dCamM
1.75
1.5
1.25
Hypotensive episodes Cramps Headache
13 (11) 3 (2.6) 4 (3.4)
7 (6) 1 (0.8) 2 (1.7)
15 (12.8)
4 (3.4)
0
The values given are the absolute number of events and in brackets events per 100 dialysis sessions.
Discussion
From the studies by Slatopoisky and co-workers it has been roidism [11]. Recently, new phosphate intestinal binders have known that control of the serum phosphate level is of great been proposed to replace Al(OH)3 because of the latter's importance in the treatment and prevention of hyperparathy- well-recognized toxicity [12, 13]. Although Ca acetate may be
636
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
Table 2. Dialysis characteristics and dose during the one year followup of the study in both groups (control group dialyzed with 1.5 mM dCa and study group dialyzed with 1.25 mi dCa) Month
0
Study group dCa mmol/liter
1.5
QB mI/mm
REC % Kr/V
4
consequence the iCa in the blood taken from the blood inlet was
12
similar in HDF versus HD. Confirming this, Malberti and
1.25
ing HDF with Ca free infusate. Goldsmith et al in 1974 [23] studied the Ca flux during hemodialysis and showed that there is a significant correlation between serum phosphate levels and Ca transfer from the dialysate to the blood. Although in our
8
Surian [22] observed a significant decrease in Ca when perform356 14.7 1.46
Control group dCa mmol/liter
10 2
0.07 1.5
1.25 1.25 367 8 375 10 13 1 12.8 1 1.48 0.06 1.44 0.1 1,5
REC %
377 17.5
3
Kr/V
1.57
0.07
QB mi/mm
sated by the infusion of equal amounts of ultrafiltered dialysate (containing the same Ca concentration as the dialysate). As a
11
367 4 13.5 1.48
1.5
369 16.3 0.07 1.5 2
359 8 3
13
0.1
1.51
1.5
7 4 0.1
380 8
14.6 4 1.44
0.06
more efficient [3, 14], CaCO3 remains the most commonly used binder, particularly in France where Ca acetate is not available,
However, the use of CaCO3 is limited by the induction of hypercalcemia in patients. To avoid the occurrence of hypercalcemia, the use of a low Ca dialysate has been proposed, particularly for patients with high serum Ca levels and yet uncontrolled phosphate [6, 15—17]. Such an approach has also been previously reported as successful in treating acute malignant hypercalcemia and hypertension [18]. However, concerning the intradialysis Ca kinetics and balance, a single study has been recently reported by Hou et al [19] assessing tCa balance from the dialysate in HD with low dCa [19]. With the technical progress achieved in the hemodialysis field, new dialysis membranes and techniques have become more commonly used [20]. We have recently reported the results of hemodiafiltration treatment on cardiovascular parameters and the clearances of small and large molecules [21]. However, no previous studies assessing the intrasession iCa kinetics in HD and the possible differences in HDF have been reported. Similarly, the long-term effects of lowering dCa have not been studied in HDF. In the present study, we assessed the intrasession kinetics for iCa and phosphate both during HD and HDF in the same patients, using three different dCa concentrations. We also studied the long-term effects of low dCa (1.25 mM) on blood pressure and hyperparathyroidism, and observed an increase in intact PTH levels which was not present in a group of patients maintained with 1.5 m dCa. We then treated
the patients with high dose of i.v. la(OH) vitamin D3 and obtained an equally satisfactory correction of the iPTH levels in both groups of patients.
Concerning the study of the intradialytic Ca kinetics, we observed a clear increase in iCa during the sessions using 1.75 mM dCa which was still significant with 1.5 msi dCa. These intradialytic positive Ca variations were not observed with 1.25
mM dCa. These findings are consistent with the dialysate collection studies reported by Hou et al [19]. Comparing the kinetics in HD and HDF, we observed a significantly higher
study we found this correlation as well, its r value was relatively small (0.31).
It is known that iCa is a determinant of the blood pressure [24, 25]. It is positively inotropic [26] and also controls arterial
smooth muscle contraction, modulating peripheral vascular resistances [27]. It has been previously shown that increasing iCa serum levels during dialysis result in an increase in mean arterial pressure [28]. However, while small blood pressure modifications during dialysis are statistically significant, they are frequently clinically irrelevant [29]. In our study, decreasing dCa to 1.25 m induced a minor but statistically significant decrease in diastolic blood pressure but no modifications of the systolic blood pressure. It has been demonstrated that the iCa actions to increase cardiac output and to increase systemic vascular resistance are distinguishable by the range of the iCa
level. While an increase from low iCa to normal induces predominantly cardiac modifications, a further increase from normal to high iCa results in an increase in systemic vascular resistances [30]. These results are in keeping with our data since
none of the patients included in this study was hypocalcemic and we found a significant decrease in DBP and no modification on SBP. These modifications did not translate into an impaired cardiovascular tolerance and the ultrafiltration rate was able to
be maintained at the same level with no increase in body weight.
It is interesting to note that the modifications in blood pressure observed intradialytically were also found in the long-term study by monitoring the blood pressure for 24 hours.
Again the mean of the one day record showed a significant difference in DBP and heart rate, but not in SBP. Although it is always satisfying to control DBP, whether this minor drop in
blood pressure is relevant for the patient in the long-term remains to be demonstrated. Previous reports have analyzed the benefits of using the low dCa in association with CaCO3 to control serum phosphate levels and avoid hypercalcemia [6, 15, 16]. Mactier et al [15] and Sawyer et al [16] modified dCa from patient to patient according to serum Ca levels with a dCa ranging from 1.75 to 1.05 m, and analyzed the modifications after four months of using CaCO3. While Sawyer et al [16] found a significant decrease in intact PTH, Mactier et al [15] found a 22% increase in C-terminal PTH which did not reach statistical significance. In the study by Slatopolsky et al [6] the dCa was maintained constant at 1.25 m for seven months and iPTH decreased by 20%, but again the variation was not significant. The CaCO3 dose taken by our patients was higher than those used in these reports. However, despite obtaining a stable serum total Ca which was similar in both the 1.5 and 1.25 mM dCa group, iPTH increased signifi-
sieving for iCa in HDF which shows that Ca transfers through the dialyzer are different in HD and HDF. In HDF between 15 and 20 liters of plasma water are filtered during the treatment. This convective component results in an increased clearance which is more prominent for high molecular weight compounds cantly during the phase of 1.25 mM dCa treatment. This but is also observed in small molecules [21]. Thus, the added increase in iPTH was specific for the 1.25 dCa group, as it was convection results in an increased Ca loss which is compen- not observed in the control group (dCa = 1.5), and appeared
637
Argues et al: Lowering Ca dialysate and hyperparathyroidism
A
B
14 Co
C
10
E
1.25 1.00
Ce
>
0 C) 0
-C
C,
6
0.75
Ce
0.50
0
0.25
Ce
2 Start
4
8
12
Time, months
Time, months
Fig. 5. Calcium carbonate and oral la(OH) vitamin D3 treatments during one year follow-up. Open bars correspond to the control group maintained with dCa = 1.5 m for 1 year, filled bars correspond to the study group (switched to dCa = 1.25 mM). Values are given as mean
SEM and the units are g/day/patient and jgIweekIpatient for CaCO3 and oral la(OH) vitamin D3, respectively.
Table 3. Twenty-four hour blood pressure record of the patients under study performed twice: During dCa = 1.5 mi and dCa = 1.25 mM
Mg(OH)2 was rather unsatisfactory forcing a decrease in
dCa
treated with lower dCa, we used i.v. la(OH) vitamin D3 without
1.5 mM
1.25 mi
SBP 133 126
5.8 5.3
Heart rate
DBP 80.6
3
75.2 3
89.4 4
85.3 3
The means for the total values recorded per patient were calculated and taken as single value. The mean standard error of the mean of these values is given for the population's analysis, and Wilcoxon's test for paired data was applied to assess the differences. ap < 0.05
1 a(OH) vitamin D3 doses and subsequent hyperparathyroidism
relapse [42]. Since the patients included in our study were discontinuing CaCO3. To assess the effect of the dCa on the treatment with 1 a(OH) vitamin D3, we administered the same treatment in a control group dialyzed with 1.5 mri dCa. In both groups of patients i.v. la(OH) vitamin D3 was similarly effective in decreasing iPTH and the decrease (—70%) was equivalent to those previously reported [40, 41]. Serum Ca levels increased after i.v. la(OH) vitamin D3 treatment; however, they remained within an acceptable range. 1 a(OH) vitamin D3 i.v. therapy had to be momentarily discontinued only on two occasions in each group. This confirms that when the patients
despite the stable Ca, phosphate and ALP serum levels. An acute decrease in iPTH levels has been reported during HD with 1.75 m dCa [311, and these authors have proposed this are treated with dCa of 1.5 mmM or lower, and have a
effect as a test to assess the ability to down-regulate the satisfactory phosphate and Ca levels, high doses of i.v. la(OH)
parathyroid gland. Other authors have confirmed this intradia- vitamin D3 can be safely used with no need for discontinuing lytic decrease in PTH when a positive iCa balance is produced, CaCO3. In summary, the present study shows that low Ca dialysate and have shown that PTH inhibition is temporary as the predialysis level of PTH before the next treatment is unchanged can be used both in HD and HDF with no deleterious intradi[32, 33]. Although unlikely because the iPTH decrease is not alytic events and no associated hypotensive episodes, provided protracted, it could be that the absence of such a periodic that the infusion fluid in HDF is not Ca free. An increased Ca inhibition participated in the increase in iPTH we observed after oral intake to control serum phosphate levels is allowed without inducing hypercalcemia since the positive intradialytic balance one year treatment with 1.25 mM dCa. There is increasing evidence showing that pulse therapy with is avoided. Lowering dCa to 1.25 m results in a minor but vitamin D3 derivatives suppresses secondary hyperparathyroid- statistically significant decrease in DBP which may be of some ism in dialysis patients [34]. The 1 ,25(OH)2 vitamin D3 form is benefit for the patient in the long-term. However, despite an the derivative most commonly reported. It has been used in oral increased oral Ca intake and satisfactory serum phosphate [35] and i.v. therapy both in hemodialysis [34, 36] and perito- control an increase in serum iPTH was observed with 1.25 mM neal dialysis patients [371. Alternatively, 24,25(OH)2 vitamin D3 dCa. High doses of i.v. la(OH) vitamin D3 were effective in [38] and 1 a(OH) vitamin D3 [391 have also been proposed. For reversing the iPTH increase. This latter treatment could be la(OH) vitamin D3, the first reports demonstrated good efficacy equally used in both groups, patients treated with 1.5 and 1.25 in decreasing iPTH [40, 41]; however, these authors reported an mM dCa.
increase in serum Ca which was a limiting factor for the treatment, as they used dCa ranging from 1.5 to 1.8 mM. Recently, Mornière et al [42] used i.v. la(OH) vitamin D3 in patients dialyzed with a dCa = 1.62 m, after discontinuing
CaCO3. In this report the serum phosphate control with
Acknowledgments
Dr. P.G. Kerr was a recipient of the CRB Blackburn Overseas Travelling Fellowship of the Royal Australian College of Physicians and a recipient of an overseas travelling fellowship from the Australian and
638
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
A
2.5
B
dCa=1.25mM
dCa = 1.25 mM
2.0
3.0
0
E
2.5
1.5
2.0
1.0
E Ce
0
1.5
I
dCa=1.5mM
4
Start
8
4 dCa= 1.5mM
0.5
12
Start
4
8
12
Time, months Time, months 400
C dCa = 1.25 mM
300
100
80
0 -J
200
60 100
40
dCa=1.5mM
T
0
Start
4
8
Start
12
Time, months
4
8
12
Time, months
well as IPTH (d) in control and study group, Filled circles correspond to the study group switched to dCa = 1.25 m and open triangles to the control group maintained with dCa = 1.5 m throughout the study, Values correspond to the mean SEM. (For statistical comparisons see the text.) Fig. 6. One year follow-up of tCa (a), phosphate (b), and ALP (c),
as
A dCa=1.5mM
B dCa=1.25mM 100
100
75
75
—.
i' 50
50
25
25
0•
0
Before
4 months
Before 4 months Fig. 7. Response to i.v. la(OH) vitamin D3 therapy. Left panel shows the control group and the right panel the group of patients treated with 1.25 mM dCa. The values are given as the percentage of the pre-treatment level which has been taken as 100%, It can be seen that there is a significant decrease in PTH levels in both groups.
639
Argues et al: Lowering Ca dialysate and hyperparathyroidism Table 4. Evolution of tCa, phosphate, and ALP after i.v. la(OH) vitamin D3
Before
2 Months
1 Month
3 Months
4 Months
dCa = 1.25mM tCa Phos ALP
2.42 1.75 62.8
0.05
2.51
0.04
1.69
2.72
63
0.07 0.1 7.5
2.78 1.64 59.8
0.05 0.1 5.3
2.52 1.41
0.07 0.12
7.8
2.66 2.04
1.77
0.08 0.09
58.7
7.1
2.63
0.05
2.61
1.66
0.11
1.8
64.8
7.9
61
57
0.06 0.2
2.78
0.05
1.67
8
52.5
0.09 6.3
0.08 0.08 7.9
2.72
0.05
1.74
0.2
dCa = 1.5 mM tCa Phos ALP
64.5 9
New Zealand Society of Nephrology. The authors thank Marie Thomas for her help throughout the study, and the nursing staff of the AIDER for their continuing assistance in the management of the patients and protocol execution.
Reprint requests to Angel Argues, LP9008 CNRS and Unit 249 INSERM, Centre de Recherches en Biochimie Macromoléculaire, Route de Mende 1919, 34033 Montpellier Cedex, France.
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ison of hemodialysis and hemodiafiltration: A long-term longitudinal study. Kidney mt 41:1035—1040, 1992 22. MALBERTI F, SURIAN M: lonised calcium changes and parathyroid hormone secretion in hemodiafiltration in relation to substitution fluid calcium content. Nephrol Dial Transplant (Suppl 2): 104—107, 1991
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NISELL J, WEISS L, WIDE L: Effects of serum parathyroid hormone
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Calcium kinetics and the long-term effects of lowering dialysate calcium concentration ANGEL ARGILES, PETER G. KERR, BERNARD CANAUD, JEAN Louis FLAVIER, and CHARLES MI0N LP9008 CNRS and Unit 249 INSERM, Centre de Recherches en Biochimie Macromoleculaire; UDSA. A.i.D.E.R.; and Department of Nephrology, University Hospital "Lapeyronie", Montpellier, France
Calcium kinetics and the long-term effects of lowering dialysate calcium
concentration. The optimal dialysate calcium (Ca) content for hemodialysis has been classically fixed at 1.75 m. However, this dialysate Ca concentration (dCa) with its positive intradialytic Ca balance combined with the use of CaCO3 as a phosphate binder may result in hypercalcemia. To prevent or treat hypercalcemia, a decrease in dCa has been proposed. In the present study both the acute and the long-term effects of lowering dCa were assessed. Additionally, given the results obtained after one year with low dCa the effectiveness of i.v. la vitamin D3 in lowering PTH serum levels in two groups of patients dialyzed with different dCa was also studied. (a) Ca kinetics during hemodialysis (HD) and on line hemodiafiltration (HDF) were studied in a group of nine stable patients who were sequentially treated with 1.75, 1.5 and 1.25 mM dCa. Dialysate was the same but for the dCa which was lowered
75%; P < 0.0313) in both groups within four months of treatment. This study shows that low dCa can be used both in HD and HDF with no associated clinical intolerance. However, the increase in oral Ca intake was not sufficient to prevent the stimulation of PTH secretion observed
with dCa =
1.25
m. Complementary treatment with high doses of
vitamin D derivatives reverses PTH increase both in 1.5 and 1.25 mi dCa treated patients.
Osteoarticular disease is a major concern in hemodialysis
stepwise. Na, K, tCa, ionized Ca (iCa), proteins, phosphate and pH patients. The known pathogenic factors for bone disease in this were measured from blood inlet and outlet and dialysate outlet at the population are multiple and interrelated: hyperparathyroidism, start, one hour, two hours and after the treatments. At the same time aluminum toxicity, osteomalacia and the more recently added weight, blood pressure and heart rate were recorded. The sieving of iCa was significantly different in HDF versus HD (F = 6.73; P < 0.01); dialysis-associated amyloidosis [1]. While the pathogenesis of intravenous infusion of 18 liters of filtered ultrapure dialysate compen- the latter is currently under study, important progress has been sated the Ca loss due to the convective component of HDF, as iCa was achieved in the treatment and prevention of the other three in similar at the blood inlet in HD and HDF in the three dCa tested (F = the last few years. Serum phosphate control can be obtained 2.59; NS). Intradialytic iCa kinetics measured in the blood inlet were significantly different with different dCa (P < 0.001 for 1,75 mM vs. 1.5 without the use of Al-containing phosphate binders and new mm and P < 0.001 for 1.5 m vs. 1.25 mM). A significant increase in vitamin D derivatives with different efficacy, administration post-dialysis iCa was observed with dCa of 1.75 and 1.5 while no techniques and side effects are available or under pre-clinical modification was observed with 1.25 mM dCa. (b) Regarding long-term effects of lowering dCa, seven of the nine patients acutely studied were experimentation [2—4]. However, the new trends in the treatment of hyperparathyroidism generate different problems which followed for a one year period after changing from dCa = 1.5 to dCa = 1.25 ms. A control group of six patients was maintained with dCa = 1.5 for the same period of time and with the same treatment schedule but for dCa. Total Ca, phosphate and alkaline phosphatase were assessed monthly, and phosphate binders and oral vitamin D derivative doses
require modifications of the classical approach to dialysis therapy [5]. One of the limiting factors in the use of high doses of CaCO3 in phosphate control is that of hypercalcemia. To
were adapted accordingly. Intact PTH was determined quarterly. avoid hypercalcemia a reduction in the dialysate Ca content CaCO3 oral intake was more than doubled in the low dCa group. Total (dCa) has been proposed [6]. Ca, phosphate and ALP were similar in both groups over the assessed year. However, a significant increase in PTH was observed after one year treatment with 1.25 mri dCa (94 40 vs. 296 99 pg/ml; P < 0.05) which was not observed in the dCa = 1.5 m control group (92 24 vs. 113 24 pg/mI; NS). (c) For the effects of high-dose i.v. 1 a vitamin D3 on PTH serum levels, six of the patients maintained with dCa = 1.25 mM for one year tolerated the treatment with la vitamin D3. A control group of six patients dialyzed with dCa = 1.5 m and with comparable PTH levels was submitted to identical treatment and follow-up. High dose i.v. Ia vitamin D3 resulted in a similar iPTH reduction (72 and
In the present study we wanted to compare the intrasession Ca kinetics in hemodialysis and our previously-described online hemodiafiltration system [7] using three different dCa concentrations. Besides the acute clinical consequences secondary to the lowering of dCa, long-term results were examined
in a 12 month prospective protocol. Our results show that lowering dCa to 1.25 mri is safe from the point of view of potential hypocalcemia, intradialytic events and blood pressure
control. However, a 2.8-fold increase in oral calcium intake with subsequent normalization of serum Ca levels was not Received for publication September 23, 1991 and in revised form September 30, 1992 Accepted for publication October 1, 1992
© 1993 by the International Society of Nephrology
sufficient to prevent stimulation of PTH secretion, as compared to a control group maintained with 1.5 mrt dCa. High doses of i.v. liz vitamin D3 can be given to both 1.5 and 1.25 ma't dCa treated patients with identical good results in decreasing PTH.
630
631
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
Methods
Long-term effects of using 1.25 m'i dCa
Patients. One patient was transplanted and another was Calcium kinetics and intradialytic studies transferred to another center shortly after the acute study of the Patients. Seven men and two women with stable end-stable 1.25 mri dCa. The long-term effects of lowering the dCa from renal failure gave their consent to participate in the trial. Their 1.5 to 1.25 m were therefore assessed over a one year period mean age was 53.2 4 years old (range: 31 to 72) and they had in the remaining seven patients as well as in a control group of been on kidney replacement therapy for 5.8 1.7 years. Their six patients maintained with 1.5 mri dCa throughout the study.
kidney diseases included chronic glomerulonephritis (3),
Biological parameters. Ca, phosphate and ALP were as-
chronic urinary tract infection (2), Henoch-Schonlein syndrome sessed pre-dialysis monthly. Osteocalcin and intact parathyroid (1), Wegener's disease (1), and undetermined (2). One patient hormone (iPTH) were assessed quarterly by RIA (Incstar Co, Stillwater, Minnesota, USA and Nichols Institute, San Juan was receiving labetalol as the antihypertensive treatment. Capistrano, California, USA). The variability for these tests Kidney replacement techniques. This group of patients was was 3.4% and 5.6% intra- and interassay, respectively. Phosroutinely treated with post-dilutional hemodiafiltration (HDF) phate binders and oral vitamin D derivative doses were adapted for three hours each, three times weekly with A-2008-C Freseto maintain tCa in the higher zone of the normal range (2.5 to 2.7 nius machines and HF8O polysulfone membranes (Fresenius mM) and serum phosphate lower than 1.7 mM.
AG, Bad Homburg, Germany). Blood flow was maintained Blood pressure. Interdialytic systolic and diastolic blood between 350 and 380 mllmin. Sterile, bicarbonate buffered pressures as well as heart rate were monitored for 24 hours with infusate was produced by on-line filtration of ultrapure dialysate a SpaceLabs 90207-31 blood pressure monitor (SpaceLabs Inc., as previously described [7]. Ion contents were: Na 139 mM, K Redmond, Washington, USA) during the use of 1.5 and 1.25 mM 1.5 m, Mg 0.5 mM, Cl 108 mM, HC03 36 m, and the Ca dCa in the study group. There was more than 35 readings per content was decreased from 1.75 to 1.5 and 1.25 mM. A total record. The mean of the one day record was used as the blood convective volume removal of 18 to 20 liters was used with 500 pressure for a given patient and used for analysis. ml/min dialysate flow. Weight was monitored with Gambro weigh beds (Gambro, Lund Sweden), and blood pressure was High dose 1 a(OH) vitamin D3 measured with a Dinamap 8103 (Critikon, Creteil, France). Patients. The seven patients maintained with 1.25 dCa for Dialysis dose was controlled by urea kinetics measurements more than one year, and a control group (also N = 7) with
every month according to Farrel's method [81 as detailed elsewhere [9]; a Kr/V > 1.4 with a PCR> 1 was sought. Simple hemodialysis (HD) without the convective part of HDF but using the same dialysis parameters as above was performed in all patients, with the three dCa concentrations to analyze the differences between HD and HDF.
equivalent PTH serum levels and maintained with 1.5 dCa throughout the study were included in the protocol. Oral 1 a(OH) vitamin D3 was stopped and replaced by i.v. 1 a(OH)
vitamin D3. One patient in each group did not tolerate i.v. la(OH) vitamin D3, and the analysis was performed in the remaining 12 patients separated into two groups according to Parameters. iCa, Na and K were measured with specific dCa concentration (6 patients treated with 1.5 and 6 treated with electrodes (Fresenius EH-F lonometer; the intra-assay and 1.25 mM dCa). interassay variability was <0.1% and <1%, respectively) in Protocol. la(OH) vitamin D3 (Etalpha, Leo Laboratories, blood taken from the arterial and venous sides of the blood Denmark) was administered i.v. at the end of the dialysis circuit, as well as in the dialysate taken from the outlet of the session. The initial dose was 1 .tg (x3/week) which was dialyzer, at the start, one hour, two hours, and at the end of the increased stepwise weekly by I g until a total dose between 6 three-hour dialysis session. Total Ca (tCa) was manually deterto 9 gIweek was given. iCa, tCa, phosphate and ALP were mined by fluorometric measurement of calcein reaction with an assessed weekly. The la(OH) vitamin D3 doses were adapted intra-assay and interassay variability <1%. At the same time according to the predialysis serum iCa levels with the aim of phosphate, total protein and bicarbonate were measured with a maintaining pre-dialysis iCa levels of 2.5 to 2.7 mrvi. Intact PTH Kone autoanalyzer (KONE mc, Finland). and osteocalcin serum levels were assessed monthly. This Protocol of calcium kinetics assessment. The patients were study was conducted for four months at the end of the one year maintained on 1.75 dCa for more than three months, then Ca follow-up with varied dCa.
kinetics were assessed in three consecutive sessions (twice using HDF and a last one with isolated HD). Urea kinetic assessment was performed the consecutive week and the dCa
changed to 1.5 m the week after, with assessment of Ca kinetics in the same way (3 consecutive sessions: 2 HDF and 1 isolated HD) 12 weeks after decreasing dCa to 1.5 mM. Identical
assessment was carried out when the patients were changed from 1.5 to 1.25 mrvi dCa.
Blood pressure and dialysis tolerance. Intradialytic blood
Statistics The Statistical Analysis System package (S.A.S., 1984, Cary, North Carolina, USA) was used. Comparison between two or three groups with several data points each, on a longitudinal basis, was performed with the analysis of the variance using
Fisher's F value. This applied for intrasession kinetics and blood pressure studies (3 different groups with 4 data points
pressure, pulse and weight were recorded before, one hour, two each) and long-term assessment of lowering dCa (2 groups with hours, and at the end of the dialysis session. Intrasession events 12 data points) and subsequent treatment with la(OH) vitamin were recorded during a one month period while the patient was D3 (2 groups with 4 data points). Longitudinal differences treated with the three different dCa concentrations. The results between two given data points were compared with the Student's t-test (normally distributed values) or with Wilcoxon's are expressed as events per 100 dialysis sessions.
632
Argues et a!: Lowering Ca dialysate and hyperparat/zyroidis,n
A Blood inlet
B Blood outlet
1.7
1.5
1.4
0 E
00 a) N
0
00 a)
1.2
0
0
1
I
I
2
3
I 1
Time, hours
C Di-Do
3
hours
1.5
£
1.4.
0 E E
.15
0a) N C
2
o Dialysate outietTime
.20
a)
1.3 1.2
-r
E E
1.4
N C
1.1
0
..D
E E
1.3
0 Ca
.10
1.3.
D
a) N
0 1.2. C
0 .05
.
1.1
0
1
2
3
Time, hours
0
1
2
3
Time, hours
Fig. 1. iCa kinetics during HDF wit/i three different dCa (1.75, 1.5 and 1.25 mM). Arterial (A), venous (B), loss of calcium from dialysate (Di-Do) (C) and dialysate outlet (D) concentrations are plotted (1.75 mai dCa is plotted as filled triangles and dashed line, 1.5 mat dCa as open squares and
dotted line and 1.25 mat dCa as filled circles and solid line).
test for paired data (not Gaussian distributions). Correlations between numeric variables were tested with Pearson's r value and regression analysis was performed when appropriate. The values are given as mean standard error of the mean and a P <0.05 is considered to be statistically significant. Results
Intradialysis studies Ca and phosphate kinetics. The changes in iCa in the course
of HDF for the three dialysate concentrations are shown in
Figure 1. Arterial iCa concentrations were significantly lower as
the dCa was reduced to 1.5 m and to 1.25 mat (F = 114; P < 0.0001). Sequentially analyzing the modifications in the course of dialysis, we observed a significant rise in iCa with dCa of 1.75
and 1.5 m (before vs. after comparison by Student's i-test for
paired data: t = 5.77; P < 0.0004 and t = 4.43; P < 0.003, respectively), while with 1.25 mre dCa, iCa did not change significantly (t = —1.21; NS). The venous blood and dialysate
outlet followed similar trends. The uptake of Ca from the dialysate was different with the three dCa (F 55.6; P <
633
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
A Blood inlet
B Blood outlet
1.7
1.5
1.6
1.4
0
E E
1.3
I
0Va)
______ __e_#._eeaee
1.5
...D
1.4
a)
N C
1.2
0
1.1
1.3 1.2
T
I
0
1
•
I
I
I
I
2
3
0
1
Time, hours
o Dialysate outlet
1.5
.20 a)
0 .15
0
0Va)
0V
i
1.4
E E
E E
N C
3
Time, hours
C Dinlet—Doutlet
a)
I 2
.10
1.3
......
w N C
D
0 1.2
0 .05
1.1
• 0
•
—..-___•___--I
J
I
I
I
I
I
I
1
2
3
0
1
2
3
Time, hours Time, hours Fig. 2. iCa kinetics during HD wit/i three different dCa (1.75, 1.5 and 1.25 mM). Arterial (A), venous (B), loss of calcium from dialysate (Di-Do) (C), and dialysate outlet (D), concentrations are plotted (1.75 mri dCa is plotted as filled triangles and dashed line, 1.5 mss dCa as open squares and dotted line and 1.25 ms dCa as filled circles and solid line).
0.0001); with 1.25 mt dCa it was small (0.06 0.008 mmollliter) and altered little during the course of the dialysis, while with 1.75 and 1.5 mi dCa it was higher and tended to decrease (Fig.
significantly between HD and HDF (F =
2.59;
NS). The
intradialysis kinetics of iCa followed the same trend in HD and HDF except for the sieving of iCa (Fig. 2). The serum phosphate levels (blood inlet and outlet) were not 1C). The sieving of iCa [dialysate outlet (Do)Iblood inlet (Bill was significantly different as the dCa was lowered (F = 1.5; NS) significantly different in HDF when compared to HD alone (F = (Fig. 3). As expected, the reduction in serum phosphate in the 6.73; P <0.01); however, this was compensated in HDF by the course of dialysis was dependent on the initial serum phosphate infusion of 18 liters containing the same Ca concentration of the level (Pearson's, r = 0.83; P < 0.0001). However, this reduction
dialysate. Thus, the iCa at the blood inlet did not differ also correlated with HC03 (r =
0.53;
P < 0.0001), but the
634
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
2). It can be observed that the dialysis dose given to these patients is largely greater than that advised by the NCDS study [10], and it was similar in both groups. Medications. The treatment with CaCO3 and la(OH) vitamin D3 are represented in Figure 5. It can be seen that there was a 2.8-fold increase in the amount of CaCO3 taken while the study progressed after dCa was lowered to 1.25 m. After a one year follow-up, the dose of CaCO3 administered was 12.6 1 and 6.57 1.9 g/day/patient in the groups treated with 1.25 and 1.5 mM dCa, respectively. At the same time Al(OH)3 was com-
2.0
1.5
pletely withdrawn in both groups. Oral 1 a(OH) vitamin D3
o
remained stable during the follow-up period (the extreme values were 1 and 0.86 p,glweek/patient for the study group and 0.96 and 0.67 pg/week/patient for the control group).
1.0
a-
Blood pressure report. None of the patients included in the low dCa group was receiving antihypertensive drugs. The
0.5
24-hour blood pressure records are detailed in Table 3. Systolic blood pressure was unchanged while decreasing dCa from 1.5
m to 1.25 m. By contrast, diastolic blood pressure and heart 0
1
2
3
Time, hours
Fig. 3. Intradialytic modifications of serum phosphate level during HDF. The three different lines correspond to 1.75, 1.5 and 1.25 mM dCa (1.75 msi dCa is plotted as filled triangles and dashed line, 1.5 msi dCa as open squares and dotted line and 1.25 msi dCa as filled circles and solid line).
rate decreased significantly when the patients were switched to
1.25 mrvi dCa (Wilcoxon test P < 0.0469 and P < 0.0313, respectively). Biochemistry. No significant variations were observed in tCa, phosphate and ALP (Fig. 6A, B, and C). tCa was stable during
the one year period (F = 0.9; NS) with values which ranged from 2.38 to 2.53, and was similar in both groups (F = 0.01; NS). Phosphate was also stable (F = 0.49; NS) and similar in both groups (F = 2.78; NS), ranging from 1.5 to 1.89 mmol/liter.
clinical significance of this is uncertain. A weak but significant correlation between the serum phosphate level and iCa sieving (Do/Bi) was observed(r = 0.3 15; P <0.0001). However, it must be pointed out that although the phosphate levels did not alter significantly in the course of the study, the amount of phosphate binders taken by the patients increased (see below), and thus definite conclusions regarding the interrelationship of the serum phosphate and the dCa are difficult to draw. Blood pressure and dialysis tolerance. Figure 4 shows intradialytic changes in systolic and diastolic blood pressure as well
Alkaline phosphatases showed opposite trends in the two groups: while the patients treated with dCa = 1.25 m increased ALP the patients with dCa = 1.5 m decreased their ALP serum levels. However, Wilcoxon's test for paired data was not significant for either group. Similarly, the analysis of the variance did not show statistical differences between the groups (F = 0.21; NS) or over the time of the study period (F = 0.01; NS).
Concerning iPTH values, although initially similar, they
showed a significant increase in the study group over the year (Wilcoxon test; P < 0.047), while the control group remained as heart rate during HDF with the three different dCa. A very stable (Fig. 6D). As a consequence iPTH was statistically decrease in both SBP and DBP during the session was observed different in both groups (F = 4.76; P < 0.036).
which was reversed with fluid restitution at the end of the
dialysis. The heart rate decreased after the start of the session and started to increase from the second hour to compensate for the weight loss. The same patterns were observed with the three different dCa concentrations. DBP significantly decreased when lowering dCa to 1.25 mrvi (F = 4.6; P < 0.01). In contrast, decreasing dCa had no effect on SBP (F = 2.5; NS). The intradialytic events most frequently recorded were hypotension, cramps and headache. As it can be seen in Table 1, the average occurrence of intradialytic events was very low: 10 hypotensive episodes, 2.2 cramps and 1.7 headaches per 100 dialysis sessions, respectively. Although headaches disappeared with dCa = 1.25 m, because of the very low occurrence, the clinical relevance of these variations is not clear.
High dose of i.v. la(OH) vitamin D3 High dose i.v. la(OH) vitamin D3 was effective in lowering iPTH regardless of the dCa. As shown in Figure 7, after four months of treatment, iPTH clearly decreased in both the group maintained with dCa = 1.5 and the group switched to dCa = 1.25 m by 75 9 and 72 9%, respectively. The absolute values were 237 69 pg/liter and 271 150 pg/liter before starting i.v. 1 a(OH) vitamin D3 therapy for the 1.25 dCa and the 1.5 dCa groups, respectively; at the end of the study iPTH was 72 36 and 73 55 pg/liter, respectively. The levels reached with the i.v. 1 a(OH) vitamin D3 treatment were similar to those
observed in the same population 16 months before while they were treated with dCa = 1.5 m. Treatment with i.v. la(OH) vitamin D3 had to be momentarily stopped because of hyperLong-term effects of using 1.25 m dCa phosphatemia on two occasions in each group. No differences were observed in osteocalcin levels either Dialysis dose. The dialysis characteristics and delivered dose as measured by urea kinetic modeling were stable throughout between the groups or after i.v. la(OH) vitamin D3 treatment the follow-up period in both the study and control group (Table (24 3 and 24 5 tg/liter at the start and 24 5 and 28 12
635
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
A
B
160 90
150' E E
140•
a.
a(I)
80'
130 70. 120.
T
•
U
U
U
0
1
2
3
0
Time, hours
1
2
3
Time, hours
90 E a) in ca
80
70
0
1
2
3
Time, hours
pg/liter, respectively, in the study and control groups after 4 months). The evolution of tCa, phosphate and ALP is presented in Table 4. There was a significant increase in tCa in the dCa 1.25 group (P < 0.05). The ALP tended to increase in both 1.25 and dCa = 1.5 mM groups (17.3% and 10% in dCa groups, respectively); however, this increase was not significant.
Fig. 4. Intradialytic changes in SBP, DBP and heart rate with the three different dCa (1.75 m dCa is plotted as filled triangles and dashed line, 1.5 msi dCa as open squares and dotted line and 1.25 mM dCa as filled circles and solid line). Table 1. Intradialysis morbidity during 117 HDF sessions
dCamM
1.75
1.5
1.25
Hypotensive episodes Cramps Headache
13 (11) 3 (2.6) 4 (3.4)
7 (6) 1 (0.8) 2 (1.7)
15 (12.8)
4 (3.4)
0
The values given are the absolute number of events and in brackets events per 100 dialysis sessions.
Discussion
From the studies by Slatopoisky and co-workers it has been roidism [11]. Recently, new phosphate intestinal binders have known that control of the serum phosphate level is of great been proposed to replace Al(OH)3 because of the latter's importance in the treatment and prevention of hyperparathy- well-recognized toxicity [12, 13]. Although Ca acetate may be
636
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
Table 2. Dialysis characteristics and dose during the one year followup of the study in both groups (control group dialyzed with 1.5 mM dCa and study group dialyzed with 1.25 mi dCa) Month
0
Study group dCa mmol/liter
1.5
QB mI/mm
REC % Kr/V
4
consequence the iCa in the blood taken from the blood inlet was
12
similar in HDF versus HD. Confirming this, Malberti and
1.25
ing HDF with Ca free infusate. Goldsmith et al in 1974 [23] studied the Ca flux during hemodialysis and showed that there is a significant correlation between serum phosphate levels and Ca transfer from the dialysate to the blood. Although in our
8
Surian [22] observed a significant decrease in Ca when perform356 14.7 1.46
Control group dCa mmol/liter
10 2
0.07 1.5
1.25 1.25 367 8 375 10 13 1 12.8 1 1.48 0.06 1.44 0.1 1,5
REC %
377 17.5
3
Kr/V
1.57
0.07
QB mi/mm
sated by the infusion of equal amounts of ultrafiltered dialysate (containing the same Ca concentration as the dialysate). As a
11
367 4 13.5 1.48
1.5
369 16.3 0.07 1.5 2
359 8 3
13
0.1
1.51
1.5
7 4 0.1
380 8
14.6 4 1.44
0.06
more efficient [3, 14], CaCO3 remains the most commonly used binder, particularly in France where Ca acetate is not available,
However, the use of CaCO3 is limited by the induction of hypercalcemia in patients. To avoid the occurrence of hypercalcemia, the use of a low Ca dialysate has been proposed, particularly for patients with high serum Ca levels and yet uncontrolled phosphate [6, 15—17]. Such an approach has also been previously reported as successful in treating acute malignant hypercalcemia and hypertension [18]. However, concerning the intradialysis Ca kinetics and balance, a single study has been recently reported by Hou et al [19] assessing tCa balance from the dialysate in HD with low dCa [19]. With the technical progress achieved in the hemodialysis field, new dialysis membranes and techniques have become more commonly used [20]. We have recently reported the results of hemodiafiltration treatment on cardiovascular parameters and the clearances of small and large molecules [21]. However, no previous studies assessing the intrasession iCa kinetics in HD and the possible differences in HDF have been reported. Similarly, the long-term effects of lowering dCa have not been studied in HDF. In the present study, we assessed the intrasession kinetics for iCa and phosphate both during HD and HDF in the same patients, using three different dCa concentrations. We also studied the long-term effects of low dCa (1.25 mM) on blood pressure and hyperparathyroidism, and observed an increase in intact PTH levels which was not present in a group of patients maintained with 1.5 m dCa. We then treated
the patients with high dose of i.v. la(OH) vitamin D3 and obtained an equally satisfactory correction of the iPTH levels in both groups of patients.
Concerning the study of the intradialytic Ca kinetics, we observed a clear increase in iCa during the sessions using 1.75 mM dCa which was still significant with 1.5 msi dCa. These intradialytic positive Ca variations were not observed with 1.25
mM dCa. These findings are consistent with the dialysate collection studies reported by Hou et al [19]. Comparing the kinetics in HD and HDF, we observed a significantly higher
study we found this correlation as well, its r value was relatively small (0.31).
It is known that iCa is a determinant of the blood pressure [24, 25]. It is positively inotropic [26] and also controls arterial
smooth muscle contraction, modulating peripheral vascular resistances [27]. It has been previously shown that increasing iCa serum levels during dialysis result in an increase in mean arterial pressure [28]. However, while small blood pressure modifications during dialysis are statistically significant, they are frequently clinically irrelevant [29]. In our study, decreasing dCa to 1.25 m induced a minor but statistically significant decrease in diastolic blood pressure but no modifications of the systolic blood pressure. It has been demonstrated that the iCa actions to increase cardiac output and to increase systemic vascular resistance are distinguishable by the range of the iCa
level. While an increase from low iCa to normal induces predominantly cardiac modifications, a further increase from normal to high iCa results in an increase in systemic vascular resistances [30]. These results are in keeping with our data since
none of the patients included in this study was hypocalcemic and we found a significant decrease in DBP and no modification on SBP. These modifications did not translate into an impaired cardiovascular tolerance and the ultrafiltration rate was able to
be maintained at the same level with no increase in body weight.
It is interesting to note that the modifications in blood pressure observed intradialytically were also found in the long-term study by monitoring the blood pressure for 24 hours.
Again the mean of the one day record showed a significant difference in DBP and heart rate, but not in SBP. Although it is always satisfying to control DBP, whether this minor drop in
blood pressure is relevant for the patient in the long-term remains to be demonstrated. Previous reports have analyzed the benefits of using the low dCa in association with CaCO3 to control serum phosphate levels and avoid hypercalcemia [6, 15, 16]. Mactier et al [15] and Sawyer et al [16] modified dCa from patient to patient according to serum Ca levels with a dCa ranging from 1.75 to 1.05 m, and analyzed the modifications after four months of using CaCO3. While Sawyer et al [16] found a significant decrease in intact PTH, Mactier et al [15] found a 22% increase in C-terminal PTH which did not reach statistical significance. In the study by Slatopolsky et al [6] the dCa was maintained constant at 1.25 m for seven months and iPTH decreased by 20%, but again the variation was not significant. The CaCO3 dose taken by our patients was higher than those used in these reports. However, despite obtaining a stable serum total Ca which was similar in both the 1.5 and 1.25 mM dCa group, iPTH increased signifi-
sieving for iCa in HDF which shows that Ca transfers through the dialyzer are different in HD and HDF. In HDF between 15 and 20 liters of plasma water are filtered during the treatment. This convective component results in an increased clearance which is more prominent for high molecular weight compounds cantly during the phase of 1.25 mM dCa treatment. This but is also observed in small molecules [21]. Thus, the added increase in iPTH was specific for the 1.25 dCa group, as it was convection results in an increased Ca loss which is compen- not observed in the control group (dCa = 1.5), and appeared
637
Argues et al: Lowering Ca dialysate and hyperparathyroidism
A
B
14 Co
C
10
E
1.25 1.00
Ce
>
0 C) 0
-C
C,
6
0.75
Ce
0.50
0
0.25
Ce
2 Start
4
8
12
Time, months
Time, months
Fig. 5. Calcium carbonate and oral la(OH) vitamin D3 treatments during one year follow-up. Open bars correspond to the control group maintained with dCa = 1.5 m for 1 year, filled bars correspond to the study group (switched to dCa = 1.25 mM). Values are given as mean
SEM and the units are g/day/patient and jgIweekIpatient for CaCO3 and oral la(OH) vitamin D3, respectively.
Table 3. Twenty-four hour blood pressure record of the patients under study performed twice: During dCa = 1.5 mi and dCa = 1.25 mM
Mg(OH)2 was rather unsatisfactory forcing a decrease in
dCa
treated with lower dCa, we used i.v. la(OH) vitamin D3 without
1.5 mM
1.25 mi
SBP 133 126
5.8 5.3
Heart rate
DBP 80.6
3
75.2 3
89.4 4
85.3 3
The means for the total values recorded per patient were calculated and taken as single value. The mean standard error of the mean of these values is given for the population's analysis, and Wilcoxon's test for paired data was applied to assess the differences. ap < 0.05
1 a(OH) vitamin D3 doses and subsequent hyperparathyroidism
relapse [42]. Since the patients included in our study were discontinuing CaCO3. To assess the effect of the dCa on the treatment with 1 a(OH) vitamin D3, we administered the same treatment in a control group dialyzed with 1.5 mri dCa. In both groups of patients i.v. la(OH) vitamin D3 was similarly effective in decreasing iPTH and the decrease (—70%) was equivalent to those previously reported [40, 41]. Serum Ca levels increased after i.v. la(OH) vitamin D3 treatment; however, they remained within an acceptable range. 1 a(OH) vitamin D3 i.v. therapy had to be momentarily discontinued only on two occasions in each group. This confirms that when the patients
despite the stable Ca, phosphate and ALP serum levels. An acute decrease in iPTH levels has been reported during HD with 1.75 m dCa [311, and these authors have proposed this are treated with dCa of 1.5 mmM or lower, and have a
effect as a test to assess the ability to down-regulate the satisfactory phosphate and Ca levels, high doses of i.v. la(OH)
parathyroid gland. Other authors have confirmed this intradia- vitamin D3 can be safely used with no need for discontinuing lytic decrease in PTH when a positive iCa balance is produced, CaCO3. In summary, the present study shows that low Ca dialysate and have shown that PTH inhibition is temporary as the predialysis level of PTH before the next treatment is unchanged can be used both in HD and HDF with no deleterious intradi[32, 33]. Although unlikely because the iPTH decrease is not alytic events and no associated hypotensive episodes, provided protracted, it could be that the absence of such a periodic that the infusion fluid in HDF is not Ca free. An increased Ca inhibition participated in the increase in iPTH we observed after oral intake to control serum phosphate levels is allowed without inducing hypercalcemia since the positive intradialytic balance one year treatment with 1.25 mM dCa. There is increasing evidence showing that pulse therapy with is avoided. Lowering dCa to 1.25 m results in a minor but vitamin D3 derivatives suppresses secondary hyperparathyroid- statistically significant decrease in DBP which may be of some ism in dialysis patients [34]. The 1 ,25(OH)2 vitamin D3 form is benefit for the patient in the long-term. However, despite an the derivative most commonly reported. It has been used in oral increased oral Ca intake and satisfactory serum phosphate [35] and i.v. therapy both in hemodialysis [34, 36] and perito- control an increase in serum iPTH was observed with 1.25 mM neal dialysis patients [371. Alternatively, 24,25(OH)2 vitamin D3 dCa. High doses of i.v. la(OH) vitamin D3 were effective in [38] and 1 a(OH) vitamin D3 [391 have also been proposed. For reversing the iPTH increase. This latter treatment could be la(OH) vitamin D3, the first reports demonstrated good efficacy equally used in both groups, patients treated with 1.5 and 1.25 in decreasing iPTH [40, 41]; however, these authors reported an mM dCa.
increase in serum Ca which was a limiting factor for the treatment, as they used dCa ranging from 1.5 to 1.8 mM. Recently, Mornière et al [42] used i.v. la(OH) vitamin D3 in patients dialyzed with a dCa = 1.62 m, after discontinuing
CaCO3. In this report the serum phosphate control with
Acknowledgments
Dr. P.G. Kerr was a recipient of the CRB Blackburn Overseas Travelling Fellowship of the Royal Australian College of Physicians and a recipient of an overseas travelling fellowship from the Australian and
638
Argues et a!: Lowering Ca dialysate and hyperparathyroidism
A
2.5
B
dCa=1.25mM
dCa = 1.25 mM
2.0
3.0
0
E
2.5
1.5
2.0
1.0
E Ce
0
1.5
I
dCa=1.5mM
4
Start
8
4 dCa= 1.5mM
0.5
12
Start
4
8
12
Time, months Time, months 400
C dCa = 1.25 mM
300
100
80
0 -J
200
60 100
40
dCa=1.5mM
T
0
Start
4
8
Start
12
Time, months
4
8
12
Time, months
well as IPTH (d) in control and study group, Filled circles correspond to the study group switched to dCa = 1.25 m and open triangles to the control group maintained with dCa = 1.5 m throughout the study, Values correspond to the mean SEM. (For statistical comparisons see the text.) Fig. 6. One year follow-up of tCa (a), phosphate (b), and ALP (c),
as
A dCa=1.5mM
B dCa=1.25mM 100
100
75
75
—.
i' 50
50
25
25
0•
0
Before
4 months
Before 4 months Fig. 7. Response to i.v. la(OH) vitamin D3 therapy. Left panel shows the control group and the right panel the group of patients treated with 1.25 mM dCa. The values are given as the percentage of the pre-treatment level which has been taken as 100%, It can be seen that there is a significant decrease in PTH levels in both groups.
639
Argues et al: Lowering Ca dialysate and hyperparathyroidism Table 4. Evolution of tCa, phosphate, and ALP after i.v. la(OH) vitamin D3
Before
2 Months
1 Month
3 Months
4 Months
dCa = 1.25mM tCa Phos ALP
2.42 1.75 62.8
0.05
2.51
0.04
1.69
2.72
63
0.07 0.1 7.5
2.78 1.64 59.8
0.05 0.1 5.3
2.52 1.41
0.07 0.12
7.8
2.66 2.04
1.77
0.08 0.09
58.7
7.1
2.63
0.05
2.61
1.66
0.11
1.8
64.8
7.9
61
57
0.06 0.2
2.78
0.05
1.67
8
52.5
0.09 6.3
0.08 0.08 7.9
2.72
0.05
1.74
0.2
dCa = 1.5 mM tCa Phos ALP
64.5 9
New Zealand Society of Nephrology. The authors thank Marie Thomas for her help throughout the study, and the nursing staff of the AIDER for their continuing assistance in the management of the patients and protocol execution.
Reprint requests to Angel Argues, LP9008 CNRS and Unit 249 INSERM, Centre de Recherches en Biochimie Macromoléculaire, Route de Mende 1919, 34033 Montpellier Cedex, France.
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