Ionic dialysance vs urea clearance in the absence of cardiopulmonary recirculation
Lucile Mercadal1,,
Sophie Tézenas Du Montcel2,
Marie-Chantal Jaudon3,
Abdelaziz Hamani1,
Hassane Izzedine1,
Gilbert Deray1,
Bernard Béné5 and
Thierry Petitclerc1,4
1 Departments of Nephrology,
2 Biostatistics,
3 Biochemistry and
4 Biophysics, Hcircôpital de la Pitié, Paris and
5 Hospal R&D Int., Lyon, France
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Abstract
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Background. Several studies have shown a slight discrepancy between ionic dialysance (D) and dialyser urea clearance (UK), even in the absence of access recirculation. As it has been suggested that this discrepancy could be due to the cardiopulmonary recirculation, we studied the relationship between these two parameters in a particular dialysis setting without cardiopulmonary recirculation.
Methods. Paired measurement of urea clearance and ionic dialysance were performed in five patients without arterio-venous access who were dialysed via an internal jugular vein twin catheter. Fifty paired measurements were used for statistical analysis. Vascular access recirculation was assessed by an ultrasound dilution technique. The measured value of ionic dialysance was corrected (D0) for the effect of vascular access recirculation and was compared with instant urea clearance calculated from the dialysate side.
Results. The difference between the paired measurements of D0 and UK (n=50) was equal to 0.6±16.9 ml/min (NS). With a statistical power of 90% and taking into account this standard deviation, this study might have shown a difference of at least 10.9 ml/min. The correlation was highly significant (P<0.0001). The discrepancy of the two parameters varied with dialysis efficiency, with a decreasing D0:UK ratio for the higher dialysis efficiency.
Conclusions. Compared with our previous results obtained in patients dialysed on arterio-venous access and performed with similar methods, the relationship between D0 and UK is modified. This difference between D0 and UK gets lower in patients dialysed on central catheters and this variance is in accordance with that expected when the influence of the cardiopulmonary recirculation on the measurement of ionic dialysance is taken into account. The limits of agreement (±2 SD) between D0 and UK (±34 ml/min, BlandAltman analysis) were higher than expected and raised questions about the accuracy of the measurement of each parameter via a central venous catheter.
Keywords: access recirculation; cardiopulmonary recirculation; haemodialysis; ionic dialysance; urea clearance
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Introduction
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Ionic dialysance is a parameter calculated from the dialysate conductivity at the dialyser inlet and outlet for two steps of inlet dialysate conductivity, and tends to become an on-line monitoring parameter of the effective dialysis dose actually delivered to the patient [13]. Because the characteristics of transfer through the dialyser and the osmotic distribution volumes in the blood, urea and electrolytes are very close, ionic dialysance is expected to equal dialyser urea clearance (UK). Ionic dialysance, however, has been reported as being slightly lower than UK [46]. As it has been suggested that this discrepancy could be due to the influence of cardiopulmonary recirculation on ionic dialysance, this study investigated the relationship between ionic dialysance and UK in a dialysis setting without cardiopulmonary recirculation. The measurements were performed in patients dialysed via a central venous catheter and without arterio-venous access.
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Subjects and methods
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All the patients dialysed in our centre via internal jugular vein twin catheters (Canaud TwinCaths, Medcomp, Harleysville, PA, USA) and without arterio-venous access (neither fistula nor graft) were tested at least twice during 1 year. Five patients were included. They were tested at most once per month.
After insertion of the catheter in the internal jugular vein, an anteroposterior chest X-ray was obtained for each patient to verify that the distal extremity of the catheter was located in the superior vena cava or the right atrium. All catheters were inserted for long-term haemodialysis and were considered to be functioning well as they delivered a blood flow up to 400 ml/min without problems regarding venous and arterial pressures. During the 1-year period, three patients were tested twice and two patients six times according to the length of time they were dialysed in our centre.
Haemodialysis was performed with an Integra® dialysis monitor (Hospal, Italy). The dialysate flow rate was set at 500 ml/min. This monitor is equipped with the Diascan® module for automatic measurement of ionic dialysance. The hollow-fibre dialyser was the usual one used for each patient (one: HG500 Hemophan, Cobe, Denver, CO, USA; two: Alwall GFS Plus 16 Hemophan, Gambro, Lund, Sweden; two: CT 190 biacetate, Baxter, Minneapolis, MI, USA). The calculation of ionic dialysance (D) was performed automatically every 30 min from measurements of dialysate conductivity according to the method previously described [2,3] and summarized in Appendix 1 and Figure 1
.

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Fig. 1. Scheme of the record of the inlet and outlet dialysate conductivity during a measurement of ionic dialysance where X1 and X2 are the two given values of inlet dialysate conductivity, Y1 and Y2 the two measured values of outlet dialysate conductivity and Cp the representation of the patient's plasma conductivity.
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UK was calculated from the dialysate side by sampling the dialysate and arterial blood just after a measurement of ionic dialysance (calculation is detailed in Appendix 2). Various dialyser blood flow rates (QB) were tested (range 200400 ml/min) for each catheter. A maximum of four blood and dialysate samples were taken during a dialysis session.
The reproducibility of UK was verified and the mass balance error for urea (MBE) was estimated using formulas detailed in Appendix 3. A MBE lower than 5% validated the measurement of UK. In order to decrease blood sampling, MBE was only calculated on 12 measurements of UK during three dialysis sessions. Subsequently, the values of D and UK higher than 85% or lower than 50% of QB were discarded because they were out of the expected range of dialysis efficiency considering all dialysis conditions.
The vascular access recirculation ratio (R) was measured using an HD01 monitor (Transonic System Inc, Ithaca, NY, USA) based on an ultrasound dilution technique [7]. For each pair of dialyser UK and ionic dialysance measurements, the vascular access recirculation ratio was assessed twice and the mean of these two values was used for statistical analysis. The HD01 monitor also provides a measure of the effective blood flow (QB) at the dialyser inlet.
The measured value of ionic dialysance (D) is related to the value of ionic dialysance of the dialyser (D0) by the following formula taking into account access recirculation (effective ionic dialysance) (equation 7 in Appendix 1):

| (|<|(|>|1|<|)|>|) |
Mean UK and ionic dialysance were compared with random effect for patient using SAS Mixed Procedure (ANOVA with random effect, SAS Institute Inc.), t-test for paired data, and BlandAltman analysis [8]. Results are expressed as mean±SD. All the tests were performed for a 0.05 significance level.
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Results
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Seventeen measurements of UK and two measurements of ionic dialysance were discarded because they were higher than 85% or lower than 50% of QB, leaving 50 paired measurements of ionic dialysance and UK for statistical analysis.
The relative error of the dosage of urea was equal to 3%. Of the 12 estimations of MBE of urea, only seven gave an error lower than 5%.
The recirculation ratio was 4.1±5.4% for an effective dialyser blood flow (QB) of 272±54 ml/min. Ionic dialysance and D0 were equal, respectively, to 174±17 and 180±19 ml/min. Taking into account patient effect, UK and D0 were highly correlated (P<0.0001). The linear regression coefficient was r=0.75. The difference between the paired measurements of D0 and UK was equal to 0.6±16.9 ml/min (180±19 vs 180±26 ml/min, NS). BlandAltman analysis is presented in Figure 2
. The limits of agreement (±2 SD) was equal to ±34 ml/min. Taking into account this standard deviation, the study including 50 measurements of D0 and UK might have indicated a statistically significant difference if it had been equal or superior to 10.9 ml/min, with a statistical power of 90%.

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Fig. 2. BlandAltman analysis between ionic dialysance corrected from the part due to access recirculation (D0) and dialyser urea clearance (UK).
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The discrepancy between ionic dialysance and UK was dependent on the dialysis efficiency (Figure 3
), even when UK was normalized by the urea distribution volume (estimated using the nomogram of Daugirdas [9]). This result was corroborated by the difference of the D0/UK ratio in two subgroups of different dialysis efficiency (D0/UK=1.06±0.11 for UK <180 ml/min vs D0/UK=0.96±0.06 for UK
180 ml/min, P<0.001, Table 1
).

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Fig. 3. Linear regression analysis between D0/UK and UK shows the influence of the dialysis efficiency on the discrepancy between the parameters. Linear regression is represented by the black line (r=0.64, P<0.05).
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Table 1. Relationship in subgroups of similar urea clearance (UK) mean values between ionic dialysance corrected from the part due to access recirculation (D0) and dialyser UK in patients dialysed on arterio-venous access [6] with the assumption of no access recirculation and in patients dialysed on central catheter
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Discussion
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Ionic dialysance has been nominated as a surrogate of UK by Polaschegg [1] and by our group [2]. Under in vitro conditions, ionic dialysance is identical to UK [2]. Recent clinical studies by our group and by others, however, have reported a discrepancy between ionic dialysance and UK in vivo [46].
Ionic dialysance is based on measurements of inlet and outlet dialysate conductivity. The relationship between the inlet and outlet dialysate conductivity is influenced by the recirculation phenomenon (Appendix 1). Because the measured value of ionic dialysance, but not that of instant dialyser UK, is influenced by recirculation, we investigated if the recirculation phenomenon can explain the discrepancy between these two parameters.
Concerning vascular access, the measured value (D) of ionic dialysance was corrected to cancel out the influence of access recirculation. This corrected value (D0) was lower than the measured value (D) by about 3%. This decrease is in agreement with previous results suggesting a decrease in ionic dialysance by about 10% for an increase in recirculation ratio of 12.5% [4]. Access recirculation was not measured in other studies performed on patients with arterio-venous fistulas, but was demonstrated to be absent in recent non-urea-based methods in patients with properly cannulated and a well-functioning 2-needle vascular access [10]. We have previously verified the absence of access recirculation in 30 of our patients with the ultrasound velocity dilution technique [11].
Cardiopulmonary recirculation also could influence ionic dialysance. During a dialysis session in a patient with an arterio-venous access, part of the blood going back to the access was not reloaded in the capillary system. In contrast, all the blood going back to the access was reloaded through the capillary system in patients dialysed on an internal jugular vein twin catheter and without an arterio-venous access. Cardiopulmonary recirculation can be detected for about 2 min, approximately 20 s after the injection of a saline bolus in the venous line [12]a shorter duration than that needed for the measurement of ionic dialysanceapproximately 6 min. This phenomenon could decrease the value of ionic dialysance compared with the direct measurement of the instant dialyser UK, as it has been demonstrated with access recirculation [1,2]. Lindsay et al. have already suggested this fact, which was, however, not demonstrated experimentally [13]. The correction for the resulting reduction in dialysis efficiency due to cardiopulmonary recirculation is made by the following equation [12]:

| (|<|(|>|2|<|)|>|) |
where QA is blood flow in the arterio-venous access, CO cardiac output flow, DAV and D0 ionic dialysance, respectively, with and without cardiopulmonary recirculation effect. With current values (CO=4800 ml/min, QA=800 ml/min), DAV is approximately equal to 190 ml/min for D0=200 ml/min. Thus, for this range of dialysance, cardiopulmonary recirculation could decrease the dialysis efficiency by about 5% during dialysis via an arterio-venous access.
When we compare the results of the present study to data we previously collected in patients dialysed via arteriovenous fistula [6], the relationship between ionic dialysance and UK is modified. The protocol of measurement of UK was the same in the two studies, as was the method of determining the dosage of urea. Considering the evolution of D0/UK with dialysis efficiency, the discrepancy of these two parameters was expected to be higher in the present study because of a higher mean UK (174±17 ml/min in the present study vs 168±25 ml/min; [6]). On the other hand, D0/UK gets colser to 1. The observed modification is near the one suggested by equation 2. This study might have indicated a difference if it had been equal or superior to 10 ml/min, as found in patients dialysed on arterio-venous fistula, with a statistical power or 90%. The difference between D0 and UK is clearly smaller on patients dialysed on central venous catheters compared with patients dialysed on arterio-venous fistula.
The influence of dialysis efficiency on D0/UK, already detected by ourselves and others, remains significant (Table 1
). This study clearly shows that this effect is not related to cardiopulmonary recirculation. One hypothesis is that the assumption of a constant plasma conductivity (Cp) during the measurement of ionic dialysance in a patient is more likely to be violated with a high UK. However, the over evaluation of D due to this effect is negligible (Appendix 4). The effect of dialysis efficiency on D0/UK also could be related to the difference between the distribution volume of urea and electrolytes in blood: this difference could become more significant with higher dialysis efficiency.
The technique of sampling from central catheters seems responsible for large errors in UK values. In fact, many values of UK appeared to be out of the expected range (17/69) and the dispersion of D0/UK was double compared with our previous study [6] (Table 1
) with a weaker linear correlation coefficient (0.75 vs 0.91). MBE confirmed many unacceptable values (5/12) of urea transfer, whereas the reproducibility of the urea dosage (3%) was acceptable. Blood sampling could be influenced by local conditions and especially by incomplete mixing in the heart cavities of blood coming from different territories [14]. In a patient dialysed via an arterio-venous access, the sampled blood is already mixed in the heart cavities. In addition, flow in the superior vena cava varies over the cardiac cycle, transiently stopping just before ventricular systole. A high level of access recirculation may occur during ventricular contraction due to the retrograde movement of blood from the right atrium. There may be no access recirculation except for this period; if so, the observed recirculation value is the average over cardiac cycles [15]. The reliability of blood sampling could be decreased by this non-homogenous and intermittent blood flow. Finally, haemolysis of blood samples occurs more frequently with catheter access than with stainless steel needles [16], and is a source of error in the electrolyte and enzyme determinations. The measurement of ionic dialysance seems less affected by these variations of dialysis conditions (only two measurements were discarded) perhaps because the evaluation of the electrolyte transfer by serial measurements of the outlet dialysate conductivity is less influenced by the local conditions.
In conclusion, the calculation of ionic dialysance from dialysate conductivity measurements takes into account recirculation, and especially cardiopulmonary recirculation, possibly explaining the discrepancy between dialyser UK and ionic dialysance found in patients dialysed on arterio-venous access. Thus, measured ionic dialysance (D) clearly seems to be a valid parameter for monitoring the effective dialysis efficiency of a patient.
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Appendices
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Appendix 1
For a given inlet dialysate conductivity (Cdin), the outlet dialysate conductivity (Cdout) depends on the patient's plasma conductivity (Cp) and on ionic dialysance (D) and is calculated by the following equation [2]:

| (|<|(|>|3|<|)|>|) |
Consequently, the measurement of two values of Cdout (Y1, Y2) for two levels of Cdin (X1, X2) allows the calculation of Cp and D, assuming that the changes in D and Cp are negligible during the short period required for the measurement of X1, Y1, X2, and Y2 (about 6 min). During each measurement of D, the value X1 of Cdin prescribed for the patient is changed automatically by the dialysis monitor by about 1 ms/cm over 2 min, defining an X2 value of Cdin (Figure 1
).
Cp and D can be calculated by the following equations:

| (|<|(|>|4|<|)|>|) |

| (|<|(|>|5|<|)|>|) |
The relationship between the inlet and outlet dialysate conductivity is influenced by the recirculation phenomenon. The greater the access recirculation, the closer the outlet dialysate conductivity from the inlet dialysate conductivity, at each of the two levels of inlet dialysate conductivity during the measurement of ionic dialysance. Thus Y1-Y2/X1-X2 tends towards 1 when increasing access recirculation and ionic dialysance tends toward zero.
The measured value of ionic dialysance (D) is related to the value of ionic dialysance of the dialyser (D0) by the following formula taking into account the access recirculation (effective ionic dialysance) [2]:

| (|<|(|>|6|<|)|>|) |
Re-arranging equation (6) yields:

| (|<|(|>|7|<|)|>|) |
Appendix 2
Urea clearance (UK) was calculated for the dialysate side according to the following formula:
where Qd is the dialysate flow at the dialyser inlet, set at 500 ml/min, Qf is the ultrafiltration rate, CdUout is the urea concentration in the spent dialysate, CwU is the plasma water urea concentration at the dialyser inlet. The concentration CwU is calculated as:
where Prot and CU are respectively the plasma total protein concentration (g/dl) and the plasma urea concentration (mmol/l) measured at the dialyser inlet.
Appendix 3
The MBE is calculated as follows:

| (|<|(|>|8|<|)|>|) |
where QBw and QBwout are the water blood flow rates at the dialyser inlet and outlet, respectively, and where CwU and CwUout are the plasma urea concentration at the dialyzer inlet and outlet respectively.
QBwout is calculated as: QBw-Qf and QBw is calculated as:

| (|<|(|>|9|<|)|>|) |
where QB, Ht and Prot are blood flow rate (calculated by ultrasound), haematocrit and plasma total protein concentration measured at the dialyser inlet.
CwUout is calculated as CUout/(1-0.01xProtout) where Protout and CUout are the plasma total protein concentration (g/dl) and the plasma urea concentration (mmol/l) measured at the dialyser outlet, respectively. CwU is calculated in the same way.
Appendix 4
If Cp is not constant, equation (3) should be written with Cp1 and Cp2. Using Cp2=Cp1+
, equation (5) becomes:

| (|<|(|>|10|<|)|>|) |
The ratio of the real value of D to the calculated value is:
If X2>X1, Cp2 is higher than Cp1 and
is positive, or X2<X1, Cp2 is lower than Cp1 and
is negative. Thus
/(X2-X1) is always positive and Dreal is lower than the calculated value of D. The ionic dialysance determined by Diascan® is over-estimated.
Because the osmotic distribution volume of sodium is the total body water volume (V), an approximation of
could be written as:
For D=200 ml/min, Cp1-X2=1 mS/cm (the maximum of what is commonly observed with X1-X2 equal to ±1 mS/cm according to Diascan operating conditions), V=40 l,
is equal to 0.01 mS/cm and the over-estimation is thus under 1%.
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Notes
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Correspondence and offprint requests to: L. Mercadal, Department of Nephrology, Hôpital de la Pitié, 83 bd de l'hôpital, F-75013 Paris, France. Email: lucile.mercadal{at}psl.ap\|[hyphen]\|hop\|[hyphen]\|paris.fr 
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Received for publication: 16. 1.01
Revision received 19. 7.01.