Nephrology Dialysis Transplantation

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1 Nephrol Dial Transplant (000) 15 [Suppl 1]: Nephrology Dialysis Transplantation On-line haemodiafiltration versus low-flux haemodialysis. A prospective randomized study V. Wizemann1, C. Lotz1, F. Techert1 and S. Uthoff 1Georg-Haas-Dialysezentrum, Giessen and Fresenius MC, Bad-Homburg, Germany Abstract Background. Current methods of renal excellent dialysis quality which apparently takes time replacement therapy lead only to an insignificant to translate into measurable clinical sequelae. removal of larger, potentially toxic, substances, which are excreted by healthy kidneys. On-line preparation of substituate from dialysate and the use of high-flux Introduction membranes allow substantial convective removal of such substances. A modified on-line haemodiafiltration There is good evidence that adequate management of method with the use of a large membrane surface and water and salt homeostasis by dialysis therapy has a a high convective part was chosen to test whether great impact on short- and long-term complications, the elimination of larger substances, such as low- such as dialysis-associated hypotension and arterial molecular-mass proteins, has a clinical impact. hypertension. There is also some evidence that removal Methods. In a prospective, controlled study over 4 of small solutes, although insufficient compared with months, 44 unselected chronic dialysis patients were the kidneys, can have important clinical repercussions. randomized to undergo either low-flux haemodialysis Weekly clearances of urea, probably a surrogate para- ( HD; n=1) or haemodiafiltration ( HDF; n=3). To meter of small uraemic toxins, even in well-dialysed eliminate confounding factors, low-molecular efficacy patients amount only to one-sixth of physiological was matched ( Kt/V 1.8), and the same membrane clearances. A further reduction in urea clearance by material ( polysulfone), ultrapure dialysate and the an underdelivery of haemodialysis ( HD) is correlated same treatment duration (4.5 h) were applied to each with a higher mortality. In a population of dialysis group. patients with a very high mortality rate each 0.1 level Results. Morbidity, mortality, blood pressure, dialysisof a Kt/V less than 1.3 was associated with a 7% associated hypotensive episodes, haematocrit and increase in mortality [1]. Interestingly, the same erythropoietin dose did not differ between the groups. USRDS data did not reveal a further benefit on The same was true for body weight and, accordingly, mortality by increased small solute clearances and a bioimpedance values, clinical hydration score, skinfold thickness, plasma albumin, prealbumin and transferrin. Kt/V greater than 1.3 and an urea reduction rate of b -Microglobulin in the plasma did not change in the more than 70%. HD group and varied between 3 and 43 mg/l throughclearance by low-flux, and even high-flux, dialysis is With larger solutes in the range of 1 60 kda the out the years. In HDF, b microglobulin decreased from similar values to 18 mg/l predialysis (P<0.01) in practically nil []. On the basis of weekly solute the first 6 months of HDF treatment and then remained clearances it can be estimated that a surrogate paraconstant during the remaining 18 months. meter for larger potential toxins, such as b -micro- Conclusion. In the absence of any clinical marker of globulin, is reduced by <% with high-flux-haemouraemic toxicity the removal of larger molecules over dialysis compared with healthy kidneys. Although the time-span of years during HDF had no clinical high-flux haemodialysis membranes have comparat- implication compared with extremely (and for routine ively high sieving coefficients for solutes of 1 0 kda, practice unrealistically) well-dialysed patients with lowhaemofiltration therapy restricts the amount of convec- the limited duration of intermittent haemodialysis/ flux HD. In the absence of any side-effects of on-line HDF and supposing that plasma b -microglobulin is tion (the principal removal route for larger solutes) to a marker of morbidity, on-line HDF ensures an maximally 100 l/week, which is still far from the weekly physiological solute clearance of 100 l. The progress in dialysis technology and the introduction of on-line methods for producing large quantities Correspondence and offprint requests to: V. Wizemann, Georg-Haasof infusate from dialysate allow the application of en- Dialysezentrum, Johann-Sebastian-Bach-Str 40, D-3539 Giessen, Germany. hanced convection. Furthermore, high-flux membranes 000 European Renal Association European Dialysis and Transplant Association

44 made of synthetic polymers such as polysulfone F60 or F80 show a tendency to absorb a considerable amount of low-molecular-mass proteins, at least under convective conditions [3].

2 44 made of synthetic polymers such as polysulfone F60 or F80 show a tendency to absorb a considerable amount of low-molecular-mass proteins, at least under convective conditions [3]. Given those technical prerequisites, it appeared worthwhile to reassess the clinical and biochemical outcome of an enforced removal of larger potential uraemic toxins in a prospective controlled study. On-line haemodiafiltration ( HDF) was modified by the use of two large haemodiafilters with the objective of exploiting a maximal dose of convection (60l/patient/session) and maximal protein adsorption to a large membrane surface. To eliminate possible confounding factors, the removal of small possible uraemic toxins was matched in the HDF and the lowflux HD group as expressed by an identical Kt/V. Secondly, to eliminate any differences by haemocompatability the same membrane material was used in both groups as well as ultrapure dialysate. Patients and methods Study design Forty-four chronic HD patients were treated with low-flux haemodialysis in a pre-phase for 3 months and were then randomized into an on-line HDF group and a HD control group. Over the following years patients were assessed clinically and biochemically every 3 months. Patients Twenty-three patients (1 male, 11 female, mean age 60±1 years) participated in the HDF group and 1 (13 male, eight female mean age 61±11 years) in the low-flux HD group. Patients were not pre-selected according to dialysis-related amyloidosis symptoms, cardiovascular disease (Table 1), nutritional status or degree of anaemia. The study design was approved by an ethics committee and all patients agreed in writing to participate. Haemodialysis methods All membranes for dialysis and haemodiafiltration purposes were used only once. Low-flux HD was performed with Fresenius 4008 machines, polysulfone F8 dialysers and bicarbonate dialysate purified by sterile filtration before entering V. Wizemann et al. the dialyser. Blood flow was ml/min, dialysate flow 500 ml/min and dialysis duration 4.5 h (range 4 7 h). HDF was performed with the on-line system as commercialized by Fresenius MC (Oberursel, Germany). The only difference to standard treatment was the introduction of a second haemo- diafilter, which was inserted after the first one ( Figure 1). Thus, two haemodiafilters ( F80-S, Fresenius MC ) had a membrane surface of 3.6 m. According to in vitro pre-tests, the most efficient way to substitute fluid was between the two haemodiafilters. Total substitution volume was targeted to 60 l/patient/session. The diffusive potential of HDF was not fully exploited (dialysate flow ml/min) in order to match Kt/V of HD. Treatment duration was the same as in HD. Study parameters Urea kinetics were calculated according to the formula of Daugirdas [4]. Urea was measured predialysis and 15 min after the cessation dialysis. Electrolytes, serum bicarbonate, serum total protein, albumin, prealbumin, transferrin and b -microglobulin were measured using routine methods. Advanced glycosylated peptides (AGE) were measured by an ELISA and CRP by a super-sensitive assay (Dr Mahiout, Hannover, Germany). Blood pressure was measured predialysis and during each hour of the procedure. Dialysisassociated hypotension was defined as the cessation of ultra- filtration and the need for extra infusate due to symptoms. Dialysis target weight was monitored by a clinical score based on the signs and symptoms of dysvolaemia [5]. In addition, total body impedance was measured every 3 months in all patients and, when necessary, echocardiography and vena cava sonography were applied to estimate an adequate range of volaemia. Thus, dialysis target weight was corrected based on the clinical score, bioimpedance and occasional echocardiographic and vena cava inferior data. Skinfold thickness was measured at 3-month intervals ( Holtain Skinfold Caliper Triceps) and appetite was scored regularly. Results Acute effects of HD and HDF on low-molecular-mass proteins b -Microglobulin was reduced by 7% during standard haemodialysis with sterile dialysate, when measured in Table 1. Cardiovascular morbidity HD (n=1) HDF (n= 3) Diabetes mellitus 3 5 Coronary artery disease 1 8 Post-myocardial infarction 5 Aorta-coronary bypass 5 4 Valve replacement 1 Cerebrovascular disease 4 Amputation 1 Some patients had more than one complication. Fig. 1. On-line HDF system.

On-line haemodiafiltration versus low-flux haemodialysis 45 a pre post-hd fashion with correction of haemocon- phosphate from 1.4 to 1.8 mmol/l, ionized calcium centration.

3 On-line haemodiafiltration versus low-flux haemodialysis 45 a pre post-hd fashion with correction of haemocon- phosphate from 1.4 to 1.8 mmol/l, ionized calcium centration. In contrast, during on-line HDF b -microglobulin plasma concentrations were reduced by 88% to 18 U/l and ipth from 9 to 57 pg/ml. Pretreatment from 1.0 to 1.3 mmol/l, alkaline phosphatase from 135 and the post-hdf concentration was near the normal HCO at month 4 in the study was 5 mmol/l inhd 3 range (4.4 mg/l ). AGE peptides decreased from and 4 mmol/l in HDF. 9.5±0.5 to 17.5±11.6 IU during standard dialysis (41% reduction) and from 39.3±8.7 to 15.±9.9 IU Course of blood pressure and dialysis-associated during HDF (61% reduction). CRP was acutely mon- hypotension itored as a marker of inflammation. When patients with pre-treatment values greater than 15 ng/ml were There was no difference in predialysis blood pressure excluded, there was a significant decrease in CRP before and after the randomization period or between during HDF (P<0.05) in contrast to HD ( Figure ). the two study groups (Figure 3). Antihypertensive medication also did not differ between HD and HDF patients. There was no sudden hypertensive episode. Long-term (4 months) results of modified HD vs The incidence of symptomatic dialysis hypotension was HDF low in both groups (Figure 4). Drop-out During the course of years, eight patients dropped- out from the HDF group (one death, two renal trans- plantations, four for personal reasons and one due to a febrile episode), and five patients dropped-out from the HD group (two deaths, three for personal reasons). Haematocrit/erythropoietin dose In the HD group 4% received erythropoietin, in HDF the figure was 40%. The weekly dose per patient ranged from 5000 to 9000 IU and did not differ between the groups. Haematocrits were remarkably stable through- out the assessment periods and in both groups ranged from 34 to 36%. Morbidity Nutrition parameters Morbidity was calculated as hospital days per 3-month period, mean values ranged from 0 to 5.8 days. At no Dialysis target weight, corrected by clinical scoring time did morbidity differ between HD and HDF and bioimpedance measurements, did not differ patients. between the groups during the study period (Figure 5). The same was true for the hydration score, appetite Dialysis-related parameters score and bioimpedance data. Skinfold thickness in HD patients was 11.8±4.4 mm in the HD group Mean dialysis duration during the year study was at the beginning and 1.6±4.8 mm at the end of 4.5±0.06 h during HD and 4.6±0.06 h during HDF. the study period; HDF patients had values of Ultrafiltration volume was 3.0±1.0 l in HD and 1.4±5.1 mm and 13.4±6.3 mm, respectively. Values 3.3±1.0 l in HDF. Urea reduction rate (URR) and between the groups did not differ at any assessment Kt/V did not differ between the groups (Table ). period throughout the study duration. npcr ranged from 1.7 to.1 g/kg/day and was not different between Standard chemistry the HD and HDF groups. Total protein was 67.4±7. g/l in the HD group at the beginning of the There was no statistical difference between the two study and 73.8±at the end. The respective values for groups at the nine assessed periods during the time the HDF group were 68.3±5.3 and 68.6±7.0 g/l. span of 7 months. Pretreatment sodium ranged from Albumin plasma concentration 3 months before 136 to 140 mmol/l, potassium from 5.0 to 5.7 mmol/l, randomization was 38.4±3.7 g/l in HD patients and Fig.. Acute effects of HD and HDF: CRP.

46 Table. Changes in urea reduction rate and Kt/V between groups V. Wizemann et al.

n.s. HDF 77 76 77 78 77 77 78 79 78 78 77 77 78 Kt/V HD 1.8 1.7 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.9 1.7 1.7 n.

Modified haemodiafiltration and standard dialysis: blood pressure (systolic/diastolic), predialysis. Fig. 4.

4 46 Table. Changes in urea reduction rate and Kt/V between groups V. Wizemann et al. Duration of study (months) URR% HD n.s. HDF Kt/V HD n.s. HDF Fig. 3. Modified haemodiafiltration and standard dialysis: blood pressure (systolic/diastolic), predialysis. Fig. 4. Modified haemodiafiltration and standard dialysis: decreases in blood pressure per 3 months. Fig. 5. Modified haemodiafiltration and standard dialysis: actual body weight.

On-line haemodiafiltration versus low-flux haemodialysis 47 39.5±3.6 in HDF patients. Twenty-four months was shown that after a time span of 6 years the after randomization albumin was 39.1±.

5 On-line haemodiafiltration versus low-flux haemodialysis ±3.6 in HDF patients. Twenty-four months was shown that after a time span of 6 years the after randomization albumin was 39.1±. g/l for application of polysulfone high-flux dialysis in contrast HD patients and 37.5±3.7 g/l for HDF patients. to low-flux dialysis can attenuate the course of dialysis- Cholinesterase activity at the end of the study period related amyloidosis [8]. It can be hypothezised that was 4317±176 U/l in the HD group and 4430±138 the HDF method, compared with high-flux HD, could U/l in the HDF group. At 3-month assessments, postpone dialysis-related amyloidosis earlier and more prealbumin ranged from 0.5±0.06 g/l to 0.34± efficiently. At least our predialysis b -microglobulin 0.08 g/l without any significant difference between the concentration was half that of Küchle et al. [8]. groups. The same was true for transferrin values with Our control group was treated with an excellent the exception at 9 months, when transferrin was mar- standard of conventional haemodialysis (high Kt/V, ginally higher in the HDF group than in the HD long duration, ultrapure dialysate, very low incidence control patients. of dialysis hypotension). Thus, it may be argued that the chance of detecting clinical differences from an b -Microglobulin almost healthy group of patients is minimal. An intermittent blood purification method, which is operb -Microglobulin in plasma, as a parameter of lowative only during 8% of a patient s life-time, is probably molecular-mass proteins, did not change in the HD not an ideal schedule. The near normal b -microglobugroup during the course of the study (Figure 6). lin plasma concentration at the end of 4.5 h HDF However, in the HDF group there was a constant indicates that there might be a compartmental problem reduction in plasma concentration until month 9 when with a highly efficient but short-acting method. the concentrations levelled at 18 mg/l. From month 3 to month 4 the differences between HD and HDF Considering the large dialyser surface area, the mem- patients were significant (P<0.01). brane porosity and the high amount of convective transport in HDF, an increased loss of valuable amino acids, peptides and proteins, e.g. albumin, can be Discussion expected and consequently malnutrition has to be discussed. Despite the unrefutable mathematical correlation between plasma albumin concentration and Studies on haemodialysis methods are characterized by their inability to demonstrate convincing clinical morbidity and mortality [9] there is considerable doubt advantages for the application of high-flux membranes that plasma albumin can be considered to be a reliable or convective solute transport, at least in stable patients marker of nutrion [10]. It appears that in non-catabolic on maintenance haemodialysis therapy [ 6,7]. This dialysis patients rather high albumin losses can be study shares this feature, although our HDF approach compensated for by an increase in liver synthesis and with a total membrane surface of 3.6 m and 60 l of hypalbuminaemia can be a consequence or part of an substitution fluid per session is far more radical than acute-phase response [11]. the Montpellier HDF method ( 1.8 m, 18 l substituric assay), there was no difference in plasma albumin Although relatively low in both groups (nephelomet- tion) or that of the Italian Cooperative Dialysis Study Group (1.6 m, 8 1 l substitution). Our on-line HDF concentrations between HD and HDF patients. approach probably represents the most ambitious Cholinesterase activity at the end of the study period attempt to date to remove low-molecular-mass proteins did not indicate increased hepatic protein synthesis in over a longer period. The negative outcome, in terms the HDF group. Body weight, skinfold thickness, of clinical differences, however, has to be discussed npcr and plasma prealbumin and transferrin, if used under three aspects. as parameters of nutritional status, described well- The -year duration of the study could be too short nourished patients in both groups. a period to detect changes. In a prospective study it In 1990 we followed up seven patients with a similar Fig. 6. Modified haemodiafiltration and standard dialysis: b -microglobulin, predialysis.

6 48 V. Wizemann et al. HDF set-up and in some of them we observed hyper- removal of larger (potential ) toxins has a clinical tensive episodes or muscle cramps [ 1], a phenomenon impact, and our rather extreme approach shares the that was totally absent in the present study. The inability of many studies to demonstrate a clinical differences cannot be explained by patient selection effect. The real surprise was the excellent nutritional and are probably due to a far better understanding and haemodynamic state of our control group treated and management of highly effective treatment modalit- using low-flux haemodialysis. However, the standard ies, such as adapting dialysate sodium individually, of our low-flux dialysis was extremely high and better control of dialysis target weight, slow increase probably very different from real-world conditions. of blood flows and bicarbonate concentrations. The Taking into account the good status of our control incidence of hypotensive episodes was low compared patients it may be argued that it is impossible to with reports from southern European countries, but achieve a further clinical improvement by any other was not different to non-study patients in our centre. method. It cannot be excluded that larger uraemic It was shown in a cross-over design that prolongation solutes exert slow effects and that the reversal of the of dialysis duration from 4 to 5 h improved haemo- situation by convective methods needs a long time to dynamic tolerance of dialysis [13]. In addition to a be noticed clinically. Since on-line HDF is wellcomparatively long dialysis treatment time we define tolerated and offers those options we see an indication an individual ultrafiltration rate according to the for those patients who have to live with extracorporeal experience with the patient s ultrafiltration tolerance renal replacement for a long duration. and consideration of the cardiovascular risk. Thus, ultrafiltration rate is fixed individually and treatment duration is flexible in the case of excessive weight gain. The identical course of blood pressure behaviour in both groups speaks against haemodynamically active References plasma factor(s) in the low-molecular mass protein 1. Held P, Port F, Wolfe R, et al. The dose of hemodialysis and range. patient mortality. Kidney Int 1996; 50: It has been shown that the intensity of haemodialysis. Cheung A. Quantification of dialysis. Blood Purif 1994; 1: 4 53 has an impact on erythropoietin response [14]. 3. Birk HW, Kistner A, Wizemann V, Schütterle G. Protein However, the relationship between dialysis efficacy, adsorption by artificial membrane materials under filtration conditions. Artif Organs 1995; 19: measured by uraemia reduction rate, and haematocrit 4. Daugirdas J. Second generation logarithmic estimates of single is primarily apparent in the under-dialysis region pool variable Kt/V: an analysis of error. J Am Soc Nephrol ( URR<65%). With our patients treated at the oppos- 1993; 4: ite end of the dialysis efficacy spectrum the addition 5. Wizemann V, Schilling M. The dilemma of assessing volume of convection to an already high dose of detoxification state the use and the limitation of a clinical score. Nephrol at the small molecular range had no further effects on Dial Transplant 1995; 10: Kerr P, Argilis A, Flavier J-L, Canaud B, Mion C. Comparison anaemia. of hemodialysis and hemodiafiltration: A long-term longitudinal The acute effect of HDF on CRP needs further study. Kidney Int 199; 41: elucidation. Compared with HD with ultrapure dialys- 7. Locatelli F, Mastrangelo F, Redaelli B, Ronco C, Marcelli D, ate, the decline in CRP during HDF treatment cannot LaGreca D, Orlandini G. Effects of different membranes and be explained by different inflammatory stimuli from dialysis technologies on patient treatment tolerance and nutri- tional parameters. Kidney Int 1996; 50: the dialysate or fully by a convective removal of CRP 8. Küchle C, Fricke H, Held E, Schiffl H. High-flux hemodialysis (MW105 kda). It can be speculated that during HDF, postpones clinical manifestation of dialysis related amyloidosis. CRP is either adsorbed to the large polysulfone surface Am J Nephrol 1996; 16: or that circulating stimuli of CRP production are 9. Lowry E, New H. Death risk in hemodialysis patients: the effected by HDF. In this context our observation that predictive value of commonly measured variables and on evalu- ation of death rate differences between facilities. Am J Kidney b -microglobulin plasma concentration, when meas- Dis 1990; 15: ured acutely pre- and post-treatment, not only declined 10. Druml W. Malnutrion is bad, but how can one detect malduring HDF, as expected, but unexpectedly also during nutrion. Nephrol Dial Transplant 1997; 1: 5 7 low-flux HD. To our knowledge this phenomenon has 11. Kaysen G, Rathore V, Shearer G, Depner T. Mechanism of not been described before and was also absent in our hypalbuminemia in hemodialysis patients. Kidney Int 1995; first HD/HDF comparison [1]. The only difference 48: Wizemann V, Birk H-W, Techert F. Effects of a modified to our earlier approach was that we used ultrapure hemodiafiltration method on low-molecular weight proteins. dialysate in low-flux HD, which is in line with the Blood Purif 1990; 8: report of the Hannover sch Münden group that the 13. Brunet P, Saingra Y, Leonetti F, Vacher-Coponat H, introduction of ultrapure dialysate lowers b -microrandomized cross-over trial of 5 h versus 4 h treatment time. Ramananrivo P, Berland Y. Tolerance of haemodialysis: a globulin concentrations in the plasma [15]. Nephrol Dial Transplant 1996; 11(Suppl. 8): Ifudo O, Feldmann J, Friedmann E. The intensity of hemodialysis and the response to erythropoietin in patients with end- Conclusions stage renal disease. N Engl J Med 1996; 334: Solf A, Janning S, Quellhorst E. b -Mikroglobulin unter In the sense of evidence-based medicine there are no Sterilisation von Dialysierflüssigkeit. Nieren- und Hochdruckkrankheiten 1997; 6: 468 hard data supporting the notion that convective (Abstract)

EFFECT OF ONLINE HAEMODIAFILTRATION ON ALL- CAUSE MORTALITY AND CARDIOVASCULAR OUTCOMES Ercan Ok, Izmir, Turkey

EFFECT OF ONLINE HAEMODIAFILTRATION ON ALL- CAUSE MORTALITY AND CARDIOVASCULAR OUTCOMES Ercan Ok, Izmir, Turkey Chair: Walter H. Hörl, Vienna, Austria Wojciech Zaluska, Lublin, Poland Prof Ercan Ok Division