Effect of ultrafiltration on peripheral urea sequestration in haemodialysis patients

Daniel Schneditz, Wojciech T. Zaluska, Alice T. Morris and Nathan W. Levin

Renal Research Institute, New York, NY, USA



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Background. Ultrafiltration (UF) is assumed to enhance urea removal during haemodialysis (HD) because of convective transport and because of contraction of urea distribution volume. However, UF-induced blood volume reduction has been hypothesized to enhance peripheral urea sequestration and post-dialysis urea rebound (PDUR), possibly reducing HD effectiveness. The effect of UF on PDUR was investigated in this study.

Methods. Nine HD patients were studied on two subsequent treatment days. The first HD was performed with UF (UF-rate=0.78±0.27 l/h), and the second treatment without UF. Serial measurements of serum water urea nitrogen concentration, arterial blood pressures (BP), and relative blood volume changes ({Delta}BV%) were obtained over the duration of HD.

Results. BP and {Delta}BV% decreased with UF (BPsys= -9%, BPdia=-8%, BPmean=-9%, {Delta}BV%=-15%) but increased or remained unchanged without UF (BPsys= 9%, BPdia=12%, BPmean=11%, {Delta}BV%=1%). PDUR was 28.6±9.6% without UF, and increased in every single patient with UF (40.7±13.2%, P<0.01). Modelled perfusion of the peripheral low-flow compartment decreased from 1.45±0.54 l/min without UF to 0.91±42 l/min with UF (P<0.05), thereby explaining an enhanced two-compartment effect and increasing PDUR.

Conclusion. The significant increase in the two-compartment effect of urea kinetics observed in current HD accompanied by UF can be explained by compensatory, intradialytic blood flow redistribution induced by blood volume reduction. Because of the link between UF and blood flow, limited solute clearance treatment modes that optimize fluid removal such as variable UF will also have favourable effects on delivered dose of dialysis.

Keywords: haemodialysis; isovolaemic haemodialysis; post-dialysis urea rebound; relative blood volume; ultrafiltration; urea kinetic modelling



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
There are both primary and secondary effects of ultrafiltration (UF) on haemodialysis (HD) urea kinetics:

Primary effects of UF on HD, which are well documented and included in most mathematical models of urea kinetics, account for a significant but modest fraction of total urea removal [1,2]. Apart from primary effects of UF, the delivered dose of dialysis has been observed to depend on degrees of hydration, haemodynamic stability, and UF rates [35]. The secondary effect of UF on HD efficiency can be explained by the regional blood flow model where urea transport is assumed as largely blood flow limited [6]. It is well accepted that UF-induced blood volume reduction elicits compensatory peripheral vasoconstriction in stable HD patients [7]. Therefore, it can be hypothesized that reduced tissue perfusion may contribute to urea sequestration in peripheral compartments. Indeed, PDUR increased with UF in five of seven patients when dialysis was performed with UF compared with dialysis without UF [5]. However, combined effects of UF were not analysed by two-compartment urea kinetic modelling. Therefore, it was the aim of this study to provide a urea kinetic analysis of the effects of UF on PDUR in a series of HD treatments performed with and without UF.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
In each patient the study was performed on two consecutive treatment days, starting with a midweek dialysis. On the first treatment day, HD was performed with UF (protocol A) with prescribed dialysis duration (t) and extracorporeal blood flow (Qb), while 48 h later, HD was repeated without UF (protocol B). In order to separate the clearance and the UF components of the standard HD treatment, the second dialysis treatment was split into an isovolaemic phase, during which HD was done without UF but with the same blood flow and dialysis duration as prescribed for the regular treatment, followed by a 2-h rebound phase without HD and without UF, and by a final and variable UF and low efficiency HD phase when excess body water was removed to reach the prescribed target weight.

Bicarbonate based HD (Na+ 143, K+ 2, Ca2+ 3.5, Mg2+ 1, HCO3- 37, Cl- 107, acetate 6 mE/l, glucose 11 mmol/l) was delivered with a volumetrically balanced dialysis machine (2008E, Fresenius Medical Care, Walnut Creek, CA, USA). The effect of UF on relative blood volume changes was measured by a non-invasive optical technique (Crit-Line Instrument, In-Line Diagnostics, Riverdale, UT, USA) [8].

Pre-dialysis blood samples (cpre) were taken from the access needle, intradialytic samples (cintra) were taken both from arterial (cintra,art) and venous (cintra,ven) blood lines. Intradialytic samples were drawn at hourly intervals at full blood flow. Post-dialysis samples were drawn from the arterial blood line at the very end of dialysis (cpost,0) and at 2, 5, 10, 20 and 30 min intervals. While cpost,0 was sampled at full Qb, subsequent samples (cpost,2 and cpost,5) were sampled at low blood flow (Qb<70 ml/min) and with HD in bypass. The patient was disconnected from the extracorporeal circulation after having taken the 5 min sample. Thereafter, post-dialytic samples were drawn from the access needle.

Serum water urea nitrogen (SWUN) was determined by the urease/conductivity technique (BUN Analyzer 2, Beckman Instruments, Inc., Brea, CA, USA). The standard deviation (SD) for repeated SWUN measurements was ±1 mg/100 ml. Plasma water Na+ was measured electrochemically (Ionometer, Fresenius Medical Care, Bad Homburg v.d.H., Germany).

Patients had given informed consent to participate in this study.

Analysis
The effect of UF on urea kinetics was measured by post-dialysis urea rebound (PDUR)


(1)
by the patient clearance time (tp) [9] given in minutes which is calculated from the post-dialysis urea rebound according to


(2)
where ceq refers to a 30 min post-dialytic sample, corrected for continuing urea generation rate (ceq=0.93xcpost,30); from the difference between single pool Kt/V (Kt/Vsp) calculated from a linearized formula [10] and equilibrated single-pool Kt/V (Kt/Vspeq) derived for the average dialysis patient from K/Vsp, and the clearance rate [11]


(1)
where {kappa} is the slope of the rate-equation given in hours [11]; and by parameter identification based on regional blood flow urea kinetic modelling as described previously [12].

Regional blood flow model
In the regional blood flow model, 20% of total body water is assumed to be located in the high-flow compartment representing the internal organs and the brain, which receive 80% of systemic blood flow. The remainder of body water, under resting conditions, is perfused by a very small fraction of the systemic blood flow. The differences in mean specific perfusion (ml/min/kg tissue water) between combined body compartments and the assumption that urea exchange in the microvasculature is mostly flow limited offers a physiologic explanation for peripheral urea sequestration during HD and post-dialytic urea rebound in HD patients. In addition to providing a physiologic approach that can explain typical degrees of urea sequestration and rebound, the model also can account for variability of peripheral urea sequestration and post-dialytic urea rebound as may be observed with manoeuvres such as intradialytic exercise [13], high dialysate sodium concentrations [14], high dialysate potassium concentrations [15] and local heating [16].

Two parameters of the regional blood flow model, post-dialysis urea distribution volume (V) and the fractional perfusion of the low flow compartment (fQL) were identified by fitting modelled intra- and post-dialytic SUN concentrations to experimental concentrations as described previously [17]. Blood side dialyser clearance (Kd) was determined from paired dialyser inflow and outflow SUN concentrations and extracorporeal blood flows (Qb) and corrected for a fractional blood urea distribution of 85%. Model parameters were assumed as described previously. The fitting procedure was performed with the Solver option provided by Microsoft Excel 5.0 minimizing the sum of squared errors between experimental and modelled data. Because of the relative importance of the rebound data, the fitting procedure was constrained to allow for a 2% deviation between fitted and experimental cpost,0 and cpost,30 concentrations.

Statistical analysis
The relative change of a value X({Delta}X%) between times t=0 and t=1 or the relative difference of a value between protocols A and B was calculated as (X1/X0-1)x100, and (XB/XA-1)x100, respectively. Data are presented as mean±SD. Differences between groups were compared by a non-parametric test (Wilcoxon signed rank test) and a probability of P<0.05 was considered significant. Correlation between parameters was studied by linear regression analysis and analysis of variance (ANOVA).



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Mean patient and treatment data in nine study patients are given in Table 1Go Treatment times (199±30 min, range 150–240 min) and dialyser clearances were the same for both protocols. As expected for the average weekly SWUN profile, pre-dialysis SWUN concentrations tended to be higher with protocol A (55.3±18.8 mg/100 ml) done midweek than protocol B (49.5±14.6 mg/ml) carried out later in the week (P=n.s.). Equilibrated post-dialysis SWUN concentrations as well as the absolute changes in post-dialysis SWUN concentrations measured as ceq-cpost were higher when treatments were accompanied by UF (protocol A) (P<0.05).


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Table 1. Mean patient and treatment data (n=9)

 
Pre-dialysis systolic, diastolic and mean arterial pressures were not different between groups; however, when accompanied by UF (protocol A), blood pressures dropped during HD, while blood pressures increased during HD without UF (protocol B), the differences between groups being significant (P<0.01) (Table 2Go). With UF (protocol A) blood volume dropped by -15.0±7.0%. Blood volume slightly increased (0.8±2.5%) without UF (protocol B). Plasma sodium concentrations were comparable with both protocols and increased during HD.


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Table 2. Blood pressures and relative blood volume changes (n=9)

 
Although there was a trend for higher equilibrated Kt/V (Kt/Vspeq) and modelled Kt/V (Kt/Vmod) in the group in which diffusive solute removal was accompanied by convective solute removal because of UF (protocol A), differences between groups were not significant (Table 3Go ). Single pool Kt/V (Kt/Vsp) was significantly higher in the patients with UF because effects of variable rebound are not considered in the single compartment approach.


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Table 3. Urea kinetic data (n=9)

 
When data were analysed by urea kinetic modelling, i.e. parameter identification of the regional blood flow model, modelled blood flow (QL) to the low flow compartment was identified to have significantly decreased during HD with UF (protocol A) when compared with HD done without UF (Table 3Go). Modelled QL decreased from 1.45±0.54 l/min without UF to 0.91±42 l/min with UF (P<0.05). PDUR increased from 28.6±9.6% without UF to 40.7±13.2% with UF (P<0.01). The increase in PDUR was observed in every single patient. Other measures of the two-compartment effect such as the patient clearance time tp [9] or the slope {kappa} of rate-equation [11] also increased with UF.



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Analysis of experimental data collected during HD carried out with and without UF showed that apart from the primary effect of UF, which refers to convective removal of urea and volume contraction, there is a physiologic component which appears to affect the two-compartment nature of urea kinetics. The observed increase in post-dialysis urea rebound in each dialysis performed with UF can be explained by increased urea sequestration in the peripheral compartment of the regional blood flow model. It is plausible to assume that this sequestration is caused by reduced peripheral perfusion occurring with UF-induced blood volume reduction, especially as a decrease in cardiac output and an increase in systemic vascular resistance is commonly observed with HD and UF [18].

PDUR is an indirect measure of the two-compartment behaviour of urea. It is largely independent of dialysis duration [19] but it increases with dialysis efficiency (K/V). Dialysis efficiency increases with UF because of convective solute removal (higher K) and because of total body water volume contraction (smaller V) [2]. Thus, a small increase in PDUR could be explained by an increase in HD efficiency. On the other hand, if regional perfusion were assumed to remain unchanged during UF, specific tissue perfusion would increase, and peripheral urea sequestration would be reduced. As a consequence, a small decrease in PDUR would be expected with increasing fluid removal and constant specific perfusion. Clearly, this is not the case.

The combined result of both primary and secondary effects of UF can be analysed by the regional blood flow model [6]. As suggested by the significant increase in PDUR a reduction in specific tissue perfusion was assumed with UF. This is in accordance with data presented elsewhere [18]. In this analysis we chose to model a reduction in the perfusion of the low flow system (QL) thereby reducing flow limited peripheral urea removal and enhancing the two-compartment effect (Figure 1Go).



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Fig. 1. Rebound and modelled perfusion of the low flow system. The relative increase in post dialysis urea rebound ({Delta}PDUR) in each patient when HD treatments were done with UF showed a significant relationship (P<0.05) with the relative decrease in perfusion of the low flow system ({Delta}QL) modelled form urea kinetic data ({Delta}PDUR=-1.1x{Delta}QL+6.6, r2=0.53).

 
Relation to other measures of the two-compartment effect
Recently, the two-compartment effect has been quantitated by relationships intended to predict equilibrated, post-dialysis urea concentration [9] or to correct single pool Kt/V for two-compartment effects [11]. These relationships were derived from the observation that the two-compartment effect was rather uniform in the standard dialysis patient treated within a wide range of low to high efficiency procedures utilizing standard dialysate compositions and constant UF rates with patients resting in a recumbent body position.

In the approach by Tattersall et al. [9] the constant two-compartment effect was described by the patient clearance time (tp=30 min), which is calculated from Equation 2. In this study, tp was higher in UF treatments (45±16 min) and lower in isovolaemic treatments (28±14 min). Overall, tp increased with the degree of the two-compartment effect. In the approach by Daugirdas et al. [11] the degree of the two-compartment effect was given by the slope of the rate-equation ({kappa}) which can be calculated from Equation 3. In the data obtained in this study, absolute slopes were steeper in UF treatments (-0.80±21 h) than in isovolaemic treatments (-0.65±0.21 h). Comparison with published data for tp (30 min) and {kappa} (-0.65 h) showed a 50 and 23% deviation for tp and {kappa}, respectively. However, the difference was not significant (one-sample sign test) and published values for tp and {kappa} to estimate the effect of urea dysequilibrium appear to be valid also in view of this study.



   Conclusion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
In all patients HD with UF increased PDUR when compared with isovolaemic HD. The regional blood flow model offers a physiologic interpretation of this observation where hypovolaemic compensation reduces peripheral blood flow thereby increasing peripheral urea sequestration. From the clinical point of view it follows that two main aspects of HD, clearance and UF, are not independent from each other, also on a physiologic basis. The relationship becomes more important as treatment times are reduced and UF rates are increased. Switching from constant to variable UF modes such as using high initial and subsequently decreasing UF rates is likely to have positive effects both on UF-induced blood volume reduction [20] and on dialysis efficiency.



   Acknowledgments
 
We thank The Dina and Raphael Recanati Foundation for financial support and In-Line Diagnostics, Riverdale, Utah, and Fresenius Medical Care, Division of Innovation & Technology for Hemodialysis, Bad Homburg, Germany for technical support of this work.



   Notes
 
Correspondence and offprint requests to: Daniel Schneditz, PhD, Department of Physiology, Graz University, Harrachgasse 21, A-58010 Graz, Austria. Back



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 

  1. Sargent JA, Gotch FA. Principles and biophysics of dialysis. In: Jacobs C, Kjellstrand CM, Koch KM, Winchester JF (eds) Replacement of Renal Function by Dialysis. Kluwer Academic Publishers, Dordrecht: 1996; 35–102
  2. Depner TA. Refinements and application of urea modeling. In: Depner TA (ed) Prescribing Hemodialysis: A Guide to Urea Modeling. Kluwer Academic Publishers, Boston/Dordrecht/ London: 1991; 167–194
  3. Ronco C, Brendolan A, Crepaldi C, La Greca G. Ultrafiltrations-Rate und Dialyse-Hypotension. Dialyse J1992; 40: 8–15
  4. Kjellstrand CM, Skröder R, Cederlöf IO, Ericsson F, Kjellstrand P. Patient related factors leading to slow urea transfer in the body during dialysis. ASAIO J1994; 40: 164–170[Medline]
  5. Zaluska W, Polaschegg HD, Wizemann V, Techert F. The effect of ultrafiltration on postdialysis rebound. EDTA/ERA Proc1994; 228 (Abstact)
  6. Schneditz D, Van Stone JC, Daugirdas JT. A regional blood circulation alternative to in-series two compartment urea kinetic modeling. ASAIO J1993; 39: M573–M577[Medline]
  7. de Vries PMJM. Plasma volume changes during hemodialysis. Semin Dial1992; 5: 42–47[ISI]
  8. Steuer RR, Harris DH, Conis JM. A new optical technique for monitoring hematocrit and circulating blood volume: Its application in renal dialysis. Dialysis Transplantation1993; 22: 260–265[ISI]
  9. Tattersall JE, Chamney P, Aldridge C, Greenwood RN. Recirculation and the post-dialysis rebound. Nephrol Dial Transplant1996; 11: 75–80[Abstract]
  10. Daugirdas JT. Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. Am Soc Nephrol1993; 4: 1205–1213[Abstract]
  11. Daugirdas JT, Schneditz D. Overestimation of hemodialysis dose depends on dialysis efficiency by regional blood flow but not by conventional two-pool urea kinetic analysis. ASAIO J1995; 41: M719–M724[Medline]
  12. Schneditz D, Daugirdas JT. Formal analytical solution to a regional blood flow and diffusion based urea kinetic model. ASAIO J1994; 40: M667–M673[Medline]
  13. Ronco C, Crepaldi C, Brendolan A, La Greca G. Inradialytic exercise increases effective dialysis efficiency and reduces rebound. Am Soc Nephrol1996; 6: 612 (Abstract)
  14. David S, Barbisoni F, Caserta C, Maffione L, Giancaspro V, Bottalico D, Cambi V. Effects of dialysate sodium concentration on post dialysis urea rebound. Nephrol Dial Transplant1996; 11: A191 (Abstract)
  15. Dolson GM, Adrogue HJ. Low dialysate [K+] decreases efficiency of hemodialysis and increases urea rebound. Am Soc Nephrol1998; 9: 2124–2128[Abstract]
  16. Depner TA, Rizwan S, Cheer AY, Wagner JG. Peripheral urea disequilibrium (PUD) during hemodialysis is temperature-dependent. Am Soc Nephrol1991; 2: 321 (Abstract)
  17. Schneditz D, Fariyike B, Osheroff R, Levin NW. Is intercompartmental urea clearance during hemodialysis a perfusion term? A comparison of two pool urea kinetic models. Am Soc Nephrol1995; 6: 1360–1370[Abstract]
  18. Bos WJ, Bruin S, van Olden RW et al. Cardiac and hemodynamic effects of hemodialysis and ultrafiltration. Am J Kidney Dis2000; 35: 819–26[ISI][Medline]
  19. Maduell F, Garcia H, Calvo C, Gorriz J, Navarro V. Analysis and prediction of urea rebound. Nephrol Dial Transplant1996; 11: A166 (Abstract)
  20. Santoro A, Mancini E, Paolini F et al. Blood volume regulation during hemodialysis. Am J Kidney Dis1998; 32: 739–748[ISI][Medline]
Received for publication: 29. 3.00
Revision received 23.11.00.