IN A STUDY that emphasizes the advantages

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1 JOURNAL CLUB Influence of High-Flux Biocompatible Membrane on Carpal Tunnel Syndrome and Mortality IN A STUDY that emphasizes the advantages of excellent record-keeping, Koda et al 1 compared the outcome of 819 patients (4,543 patientyears) who had received dialysis in a single center over a 25-year period. All patients received dialysis exclusively with conventional cellulosic membranes before 1984 and then with high-flux membranes gradually after that time. By 1995 (the end of the study), only 60% of patients were receiving dialysis with high-flux membranes. The Cox proportional hazard model was used to adjust for the major risks of survival in endstage renal disease, namely, patient age, calendar year at initiation of dialysis, gender, cause of renal failure (and specifically diabetes), and type of dialysis membrane used. This last risk factor was made a time-dependent risk because there were a number of patients who were switched from a conventional to a high-flux membrane during the study. (Incidentally, there were no patients who switched from a high-flux to a conventional membrane.) This group of membrane switchers (approximately 185 patients) represented a challenge for analysis of the data since there is usually a carry-over effect from one therapy (ie, conventional cellulosic membrane) to another (highflux biocompatible membrane). Indeed, as the authors point out, some early cases were changed to high-flux membranes because the patient was developing carpal tunnel syndrome (CTS). The authors addressed this problem by considering one of three approaches: model A, excluding such symptomatic patients, thus developing a strong bias in favor of conventional membranes (since such patients are likely to have developed their symptoms and signs while on conventional Received and accepted as submitted January 8, Address reprint requests to Raymond M. Hakim, MD, PhD, Renal Care Group, 2100 West End Ave, Suite 800, Nashville, TN rhakim@renalcaregroup.com 1998 by the National Kidney Foundation, Inc /98/ $3.00/0 Discussion: Raymond M. Hakim, MD, PhD This month s discussion... The Journal Club focuses on a recent article entitled Switch From Conventional to High-Flux Membrane Reduces the Risk of Carpal Tunnel Syndrome and Mortality of Hemodialysis Patients (Kidney Int 52: , 1997) by Yutaka Koda, Shin-ichi Nishi, Shigeru Miyazaki, Susumu Haginoshita, Tai Sakurabayashi, Masashi Suzuki, Shinji Sakai, Yasuko Yuasa, Yoshihei Hirasawa, and Tsugio Nishi. membranes); model B, including them as carryover until the time they underwent surgical carpal tunnel release (with proof of 2 m involvement); and model C, censoring them at the time they switched from one membrane to the other. In all three models, the Cox analysis indicated a reduced risk for CTS when patients were dialyzed with high-flux membranes: relative risk (RR) 0.64 (P 0.29) for model A, RR 0.50 (P F 0.05) for model B, and RR (P 0.01) for model C. Multivariate analysis of all risk factors indicated age and membrane type to be the only two important statistically significant risk factors for CTS, similar to the study by Van Ypersele et al. 2 Again, using the Cox hazard model for analysis of the impact of dialysis membrane on mortality, Koda et al found that the type of membrane had a strong impact on outcome: the RR of mortality using biocompatible high-flux membranes compared with using cellulosic membrane was (P F 0.02). Other patient characteristics also affected mortality. Thus, for every year increase in age, the RR of mortality was increased by (P F 0.01), whereas diabetic status (compared with nondiabetic status) increased the RR to 1.9 (P F 0.001) and female gender decreased the RR to (P F 0.004). The reduction in RR of mortality from using the biocompatible high-flux membrane was more marked than the results found by Hakim et al, 3 but less marked than those found by Hornberger et al American Journal of Kidney Diseases, Vol 32, No 2 (August), 1998: pp

2 JOURNAL CLUB 339 DISCUSSION Those who have followed the various criminal and civil trials of O.J. Simpson have learned that there are various legal levels of proof: conviction in a criminal case requires proof beyond a reasonable doubt, while civil cases require a more likely than not or a preponderance of evidence to prove an accusation. The article by Koda et al is one more piece of evidence in a series of recent studies 4-9 that provides a preponderance of evidence that the use of biocompatible high-flux membranes substantially reduces the morbidity, in this case CTS, and mortality of hemodialysis patients. While a prospective controlled, randomized study is the only one that can lead to proof beyond a reasonable doubt that the high-flux biocompatible membrane plays such a profound effect on the incidence of CTS and mortality (reducing the RR by approximately 40% in both outcomes), this preponderance of evidence about the role of the membrane is such that many institutional review boards (such as the one at Vanderbilt) refuse to allow any long-term studies of these cellulosic membranes. Thus, it is likely that we will never be able to obtain such a high standard of proof, at least in the United States. With that caveat, the purists would point out that a drawback of the study is that it was retrospective, nonrandomized, or noncontrolled. Having said that, there are many strengths to the study. One of the major strengths of the study is the fact that the analysis was based on the results of a single center, with presumably uniform policies of general medical care and observational techniques, such as blood pressure control, surgical care, dose of dialysis, etc; the fact that the observation period was so long (25 years) also allowed for detection of the true incidence of CTS and longitudinal follow-up of 2 m levels as well as mortality. Nevertheless, as in any clinical study, over a period of 25 years, there were several technologic variables that changed during the course of the study: the introduction of reverse osmosis, bicarbonate dialysate, volumetric control, depyrogenation of the dialysate, etc. These changes would be expected to affect both membranes equally or at least not to worsen the outcomes for conventional cellulosic dialyzers; in addition, the year of initiation of dialysis, a potential surrogate of these changes, was not a statistically significant factor (P 0.97). Thus, these technologic changes are not likely to bias the results of these outcomes. To address the issue of different patient characteristics treated with the two types of membranes, the authors used a Cox proportional hazards model. An important drawback of the Cox analysis is that it can take into account only the risk factors that we know about a priori and, in such cases, can only take into account the presence or absence of a factor, but not its severity. Thus, in accounting for diabetes, it can only analyze the presence or absence of diabetes but not its severity. It is possible, although not likely, that diabetic patients with multiple diabetic pathologies or peripheral vascular disease may have been represented in one membrane group or another. It is important to note that the authors included only a selected number of variables in their Cox proportional risk hazard model. Although they included the most important risk hazards (ie, age and presence of diabetes), other potential hazards, such as heart disease, malignancies, vascular disease, and residual renal function, were not included in the analysis. Finally, it is unfortunate that the authors did not study other outcomes, such as nutritional parameters (lean body mass, albumin level, etc) or loss of residual renal function, that may offer us a hint of the pathophysiologic relationship between membrane and outcome. Of the causes of mortality, cardiovascular disease and infectious causes were different between the patients using both membrane types. The cardiovascular mortality was 25% less and infectious mortality was 30% less in patients receiving high-flux dialysis compared with patients on conventional dialysis. These trends are similar to the differences noted by the analysis of the US Renal Data Service data. 3 This study, like many others, cannot differentiate the beneficial effects of the membrane between the high-flux or biocompatible characteristics of the membrane. It is logical to assume that the most important characteristic of the membrane in terms of the incidence of CTS is its high-flux characteristic, which allows better removal of 2 m; however, based on the myriad actions of complement activation, reactive oxygen production, and recurrent neutrophil activa-

3 340 JOURNAL CLUB tion, it is likely that the differences in cardiovascular and infectious mortality are primarily due to the biocompatibility characteristics of the membrane. 10 REFERENCES 1. Koda Y, Nishi S, Miyazaki S, Haginoshita S, Sakarabayashi T, Suzuki M, Sakai S, Yuasa Y, Hirasawa Y, Nishi T: Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 52: , De Strihou VY, Malghem JM, Maldague B, Jamart J: The Working Party on Dialysis Amyloidosis: Effect of dialysis membrane and patient s age on signs of dialysisrelated amyloidosis. Kidney Int 39: , Hakim RM, Held PJ, Stannard DC, Wolfe RA, Port FK, Daugirdas JT, Agodoa L: Effect of the dialysis membrane on mortality of chronic hemodialysis patients. Kidney Int 50: , Hornberger JC, Chernew M, Peterson J, Garber AM: A multi-variative analysis of mortality and hospital admission with high-flux dialysis. J Am Soc Nephrol 3: , Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on PAN/AN69 membrane hemodialysis: A ten year analysis. J Am Soc Nephrol 4: , Miura Y, Ishiyama T, Inomata A, Takeda T, Senma S, Okuyama K, Suzuki Y: Radiolucent bone cyst and the type of membrane used in patients undergoing long-term hemodialysis. Nephron 60: , Hakim RM, Wingard RL, Husni L, Parker RA, Parker TF III: The effect of membrane biocompatibility on plasma 2 m-microglobulin levels in chronic hemodialysis patients. J Am Soc Nephrol 7: , Parker TF III, Wingard RL, Husni L, Ikizler T, Parker RA, Hakim RM: Effect of the membrane biocompatibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 49: , Chanard J, Bindi P, Lavaud S, Toupance O, Maheut H, Cacour F: Carpal tunnel syndrome and type of dialysis membrane. BMJ 298: , Hakim RM: Clinical implications of hemodialysis membrane biocompatibility. Editorial review. Kidney Int 44: , 1993 Author s Reply: Yutaka Koda, MD WE ARE PLEASED to have an opportunity to participate in this very interesting discussion. Despite the experimental evidence supporting the superiority of a biocompatible highflux membrane, its true effect on human dialysis and the mechanisms of its clinical effect are still controversial. In particular, whether the beneficial effect of the membrane is related to improved biocompatibility or higher clearance of larger molecular weight solutes is a debatable question. SKEPTICISM REGARDING A RETROSPECTIVE STUDY Dr Hakim elaborated about the quality of the proof. A prospective randomized control study is generally considered to be the most reliable method to reach a true conclusion in regard to a From the Kidney Center of Shinraku-en Hospital, Niigata, Japan. Received and accepted as submitted May 29, Address reprint requests to Yutaka Koda, MD, Kidney Center of Shinraku-en Hospital, 1-27 Nishi-Ariake, Niigata, Japan. WG8Y-KUD@asahi-net.or.jp 1998 by the National Kidney Foundation, Inc /98/ $3.00/0 clinical issue. I do not deny its importance. Even a prospective randomized trial itself has some problems; it is extremely costly, and there are the difficulties of exact control and high drop-rate to contend with. Restricted physicians obtain the results in restricted patients. Furthermore, whether the results are really applicable to the general population still requires extensive experience. Because of these problems, even a prospective study often fails to raise complete answers to all the questions that clinical scientists really want to know. A prospective trial would not always be possible from an ethical point of view, as indicated by Dr Hakim; this situation, I suppose, is the same in every country. A series of experimental evidence about biocompatibility and flux of midsized molecules has already suggested that a high-flux biocompatible membrane is a preferable means of treatment to prevent long-term comorbid conditions and prolong survival with renal replacement therapy. Under such circumstances, our policy as dialysis physicians should be based on the following principle: the possibility of dispersing hazardous effects by a lowquality therapy should be considered more impor-

4 JOURNAL CLUB 341 tant than the loss due to a negative conclusion (ie, a high-flux biocompatible membrane has no advantages) that has been drawn with insufficient evidence. Isn t an evaluation based on observed clinical data helpful in determining better treatment? If we deal with a large number of samples, I believe many suggestions will exist even in a retrospective study. We must make an effort to remove biases with scientific methods as much as possible. We treated patients for three decades in a single center and recorded the various outcomes. We had a strong desire to interpret those outcomes with the use of a high-flux membrane as the objective evidence. Thus, we chose the Cox proportional hazard model with a timedependent covariate to evaluate membrane effects. I believe that the obtained result must have some merit. PROBLEMS OF COVARIATE INCLUSION Special cautions are needed to perform a Cox proportional hazard model. There are some covariates that either cannot be included in the model or would be difficult to include. A covariate that varies from time to time is inappropriate to deal with because the proportionality of hazard will not be assumed. Average value during the course should not be included as a covariate. We selected four unmodifiable factors (age, gender, diabetic state, and calendar year of dialysis initiation) and one modifiable factor (membrane status). 1 The endpoints we defined were also automatically determined (ie, the day carpal tunnel decompression surgery was performed and the day the patient died). Thus, membrane status could be adjusted by unmodifiable, very fundamental factors. Nutritional parameters (lean body mass, albumin, creatinine, transferrin, and so forth) were particularly important predictors of survival. We did not include them but are now preparing the result separately. Other technological factors that changed during the course of the study were very complicated and difficult to incorporate into the model operationally. We think a more sophisticated method is needed to evaluate these factors. WHY A CALENDAR YEAR IS NOT SIGNIFICANT We found that the calendar year, which could be a surrogate of many therapeutic advancements such as technology and medical care, was not a statistically significant covariate. Frankly speaking, this result was not what we expected. Every physician may think that recent progress in medication and technology must ameliorate the prognosis, but this is not as simple as it seems. One likely speculation as to the result is dialysis entry selection over time; less severe patients were selected to enter dialysis therapy in earlier years and more severe patients with complications were selected in later years. One method to correct this bias is grading the severity of the major underlying disease, which Dr Hakim has suggested. Another reason is that therapeutic advancement might have allowed patients rather nonadherent to self-control. For example, a more water-permeable membrane easily allows large volume removal during a single HD session and a more potent antihypertensive agent also allows an overhydrated state to be continued. Both of these treatments introduce an inappropriately large interdialytic weight gain resulting in cardiac overload. Charra et al 2 described this kind of vicious cycle. These might have imposed on the calendar year to be a nonresponsible covariate. TOTAL BIOCOMPATIBILITY WITH ULTRAFILTERED DIALYSATE It has been suggested that better survival and a better nutrition resulted when non-complementactivating biocompatible membranes were used in dialysis. Biocompatibility is the total effect of the interaction between blood and artificial materials resulting in an inflammatory reaction. In addition, there are several other contributing aspects in hemodialysis, including dialysate composition, dialysate purity, sterilants, anticoagulants, leaching-outs from device materials, and reuse procedures in some countries. When we discuss the biocompatibility of the membrane, the dialysate biocompatibility should also be considered, especially when using a highflux membrane that allows significant backfiltration (inflow) of dialysate into the blood stream. Endotoxin is a potent stimulant to human efferent limbs of the immunologic system. The effect of endotoxin will be multiplicative with complement activation and cytokine induction, socalled complement-cytokine connection. Since 1988, when starting high-flux membrane dialysis in our hospital, dialysate made from RO water

5 342 JOURNAL CLUB has been ultrafiltered to remove endotoxins (not stated in Dr Hakim s comment but written in our paper). 1 This is a very important point when interpreting our results. Endotoxin levels of dialysate were reduced to less than 20 pg/ml thereafter with the use of endotoxin-cut ultrafilters. 2 -microglobulin (B2M) is a responsible uremic toxin in dialysis amyloidosis. A repeated inflammatory state induced by these bioincompatible factors may possibly increase B2M. We observed reduced B2M in membrane switchers, that persisted over years. This phenomenon is considered to be due to both dialyzer flux of larger solutes and the total biocompatibility. Thus, we insist that total biocompatibility should be provided combined with membrane characteristics and microbiological dialysate purity. Our greatest concern is which factor is more responsible for morbidity and mortality: biocompatibility or permeability of larger molecular weight solutes. Unfortunately, our study cannot answer this question because almost all membrane types we used were improved both in biocompatibility and flux. Furthermore, the distinction between a complement-activating and non-complement-activating membrane is extremely difficult. Because we classified membranes depending on B2M elimination, our discussion in the paper emphasized mainly large molecular solute flux. In the annual statistics reported by the Japanese Society of Dialysis Therapy in 1997, a high B2M greater than 40mg/L is associated with higher risk of death adjusted for age, gender, diabetic state, and years on hemodialysis. 3 A 1997 presentation by H.F. Woods 4 showed the removal of larger molecular species of putative uremic toxin has survival advantages independent of membrane biocompatibility. The results of our study and the others cited here show that both biocompatibility and flux would be important. If we consider adsorptive mechanism or hemodiafiltration, both of which can remove larger solutes like factor D (a large molecule to enhance a complement alternative pathway), we can understand that biocompatibility and flux are closely related factors. Membrane biocompatibility alone is not enough. Dialysis membranes must also be considered according to flux of large molecules (B2M) and dialysate purity. Table 1. Demographic and Dialytic Therapy Comparison of the Two Reports Patient Characteristics Niigata, Shinraku-en Hospital (Koda et al 1 ) Tassin (Charra et al 5 ) Follow-up N (M/F) 819 (525/294) 445 (303/142) Mean age at start DM (%) Membrane low-flux and high-flux low-flux (cup): 100% Dialysis time (hr) Kt/V Dialysate Acetate = Bicarb. Acetate ultrafiltered FOR LONG-TERM SURVIVAL Charra et al 5 (from Tassin, France) have reported the best long-term survival data in the world. This outstanding survival was attributed to long hours of dialysis and a high Kt/V with excellent blood pressure control and no antihypertensive agents. It is interesting to note that a complement-activating membrane and acetate dialysate were exclusively used in that cohort. This suggests that membrane is less important than dose of dialysis. But let us compare our results with that of Charra and colleagues, 5,6 although it needs adjustment in the end-stage treatment policy and the decompression surgery indication for exact comparison. Demographic data and contents of dialytic therapy are compared in Table 1. The subjects of the two reports are almost comparable. Survival by Kaplan-Meier analysis is better in Tassin than ours until 15 years but reversed after 15 years (Fig 1). We speculate that there were fewer life-threatening complications in our pa- Fig 1. Patient survival in Shinraku-en Hospital 1 ( ) with every 5-year plot of Tassin 5 ( ).

JOURNAL CLUB 343 Fig 2. Incidence of carpal tunnel syndrome (%) of Shinraku-en Hospital 1 (left) and Tassin 6 (right). tients, specifically after long-term dialysis.

6 JOURNAL CLUB 343 Fig 2. Incidence of carpal tunnel syndrome (%) of Shinraku-en Hospital 1 (left) and Tassin 6 (right). tients, specifically after long-term dialysis. We would like to hypothesize that this consequence arose from the use of a high-flux biocompatible membrane and a high quality of water. Moreover, carpal tunnel syndrome is less prevalent in our patients (Fig 2). This might also be attributed to substantial removal of B2M by the larger pore size of high-flux membrane in contrast to the exclusive low-flux cellulose membranes used in study by Charra et al. QUALITY DIALYSIS High-flux treatment to eliminate larger solute and the possible interaction between biocompatibility and membrane flux has been recognized as clinically important. Our study suggests three dialytic factors are essential for quality dialysis that will reduce morbidity and mortality in treating ESRD patients: biocompatibility, flux, and dialysate purity. REFERENCES 1. Koda Y, Nishi S, Miyazaki S, Haginoshita S, Sakurabayashi T, Suzuki M, Sakai S, Yuasa Y, Hirasawa Y, Nishi T: Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 52: , Charra B: Control of blood pressure in long slow hemodialysis. Blood Purif 12: , Japanese Society for Dialysis Therapy: Multivariative analysis of the factors influencing survival of hemodialysis patients (in Japanese), in An Overview Of Regular Dialysis Treatment in Japan as of December 31, Japanese Society for Dialysis Therapy, pp Woods HF: Evidence for biocompatibility-independent effect of high-flux dialysis on improved patient survival. Nephrology 3:S415, 1997 (abstr; suppl 1) 5. Charra B, Calemard E, Ruffet M, Chazot C, Terrat JC, Vanel T, Laurent G: Survival as an index of adequacy of dialysis. Kidney Int 41: , Charra B, Calemard E, Laurent G: Chronic renal failure treatment duration and mode: Their relevance to the late dialysis periarticular syndrome. Blood Purif 6: , 1988

Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients

Kidney nternational, Vol. 52 (1997), pp. 196 111 Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients YUTAKA KODA, SHN-cH Nism,