Outcomes of hemodiafiltration based on Japanese dialysis patient registry

HEMODIALYSIS MODALITIES

Outcomes of Hemodiafiltration Based on Japanese Dialysis Patient Registry Shigeru Nakai, MD, Kunitoshi Iseki, MD, Kaoru Tabei, MD, Kazuo Kubo, MD, Ikuto Masakane, MD, Kiyohide Fushimi, MD, Kenjiro Kikuchi, MD, Toru Shinzato, MD, Tsutomu Sanaka, MD, and Takashi Akiba, MD ● Effectiveness of various therapeutic modalities was analyzed among 1,196 patients entered in the registry of the Japanese Society for Dialysis Therapy who were on hemopurification therapy as of the end of 1998 and developed dialysis-related amyloidosis during 1999. In the investigation, the effectiveness of various hemopurification modalities on the dialysis-related amyloidosis was ranked as exacerbation, unchanged, or alleviation, so as to analyze the possible relationship between the hemopurification modality and its effectiveness. The analysis was performed using a logistic regression approach, and the results were shown as “the risk of a worse therapeutic ranking” among the hemopurification modalities. The smaller “the risk of a worse therapeutic effect” was, the more effective the treatment modality. When the risk of a worse therapeutic effect for the hemodialysis patients treated by a regular membrane was put at 1.0, the risk for hemodialysis patients using high-flux membrane was 0.489, the off-line hemodiafiltration risk was 0.117, the on-line hemodiafiltration risk was 0.013, and the risk of push/pull hemodiafiltration was 0.017. For hemodialysis with a ␤2-microglobulin adsorption column, a low risk of 0.054 was found. The results indicated that hemodiafiltration therapy and simultaneous hemodialysis with ␤2-microglobulin adsorption therapy were more effective treatment for dialysis-related amyloidosis. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Amyloidosis; hemodiafiltration; ␤2-microglobulin; arthralgia.

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ATIENTS REQUIRING maintenance renal replacement therapy are increasing in number each year in Japan, and dialysis-related amyloidosis (DRA) has become a serious problem.1 It is acknowledged widely that DRA is triggered by the accumulation of uremic substances of middle to large molecular weight, such as ␤2microglobulin.2 The high-efficiency removal of these substances may be effective for the treatment and prevention of DRA. Several treatment modalities have been employed clinically for effective removal of such substances, but only a few reports investigated their effectiveness statistically on the basis of a large patient population to date.3,4 Since 1966, the Japanese Society for Dialysis Therapy has conducted an annual questionnaire From the Patient Registration Committee Headquarters of the Japanese Society for Dialysis Therapy, Tokyo, Japan. Address reprint requests to Shigeru Nakai, MD, Department of Internal Medicine, Daiko Medical Center, Nagoya University School of Medicine, 65, Tsurumai-cyou, Shouwa-ku, Nagoya, 466-0065, Japan. E-mail: s-nakai@ mta.biglobe.ne.jp © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3804-0145$35.00/0 doi:10.1053/ajkd.2001.27449 S212

survey of dialysis patients at dialysis facilities nationwide. The survey receives responses annually from more than 99% of dialysis facilities. Data on 197,213 dialysis patients across Japan were gathered in the survey conducted at the end of 1999.1 In the present study, we evaluated the effects on DRA of various hemopurification modalities based on the patient data from this nationwide database. MATERIALS AND METHODS

Survey Materials and Methods The Patient Registration Committee of the Japanese Society for Dialysis Therapy annually performs a nationwide survey on the individual patient case mix and laboratory data and important events occurring during the previous year. Completed survey forms were obtained from 3,085 (99.7%) of the 3,095 institutions surveyed in 1998. Of the surveyed facilities, 2,963 (95.7%) returned questionnaires on the status of the individual patient.5 In 1999, the survey forms were mailed out to 3,231 institutions, of which 3,220 (94.8%) replied. Of the surveyed facilities, 2,967 (91.8%) returned questionnaires on the status of the individual patient.1 There was a total of 185,322 patients on maintenance renal replacement therapy as of the end of 1998 compared with 197,213 at the end of 1999. In the 1998 survey, follow-up could be done in 181,484 patients compared with 185,688 patients in the 1999 survey.

American Journal of Kidney Diseases, Vol 38, No 4, Suppl 1 (October), 2001: pp S212-S216

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Dialysis-Related Amyloidosis Survey

therapy more than 2 years as of the end of 1999 (this was to ensure no influence from residual renal function) but not on steroid therapy as of the end of 1999. It is conceivable that the above-mentioned patients without DRA as of the end of 1998 suffered a DRA onset by the end of 1999. The background of subjects for analysis is shown in Table 1. At the end of 1999, there were 265 patients on HD-RM, 839 on HD-HFM, 70 on off-line HDF, 7 on on-line HDF, 3 on O-PPHDF, and 12 on HD-␤2MAC therapy. There were no patients on N-PPHDF or HDF-␤2MAC.

A DRA survey was conducted twice, at the time of the respective year-end 1998 and 1999 surveys. The survey covered three items: (1) presence or absence of DRA, (2) types of hemopurification methods used for DRA therapy, and (3) use or nonuse of steroid administration. The last two items applied only to the patients who replied in the affirmative regarding the presence of DRA. The DRA survey sought to determine which of the following hemopurification methods were used: hemodialysis using regular membrane (HDRM), hemodialysis using high-flux membrane (HD-HFM), on-line hemodiafiltration (on-line HDF), off-line hemodiafiltration (off-line HDF), original push/pull HDF (O-PPHDF), new version push/pull HDF (N-PPHDF), hemodialysis with ␤2-microglobulin adsorption column (HD-␤2MAC), hemodiafiltration with ␤2-microglobulin adsorption column (HDF␤2MAC), Bio-filtration (BF), and Bio-filtration using new version push/pull hemodiafiltration (BF-PPHDF). In the 1999 year-end survey, in addition to the abovementioned items, the effectiveness of the DRA therapeutic modalities was surveyed according to three response categories: alleviation, unchanged, and exacerbation. This selection was made subjectively by the physician in charge.

Analytical Method The various treatment methods were analyzed in terms of their effectiveness for DRA, which was surveyed according to three response categories (alleviation, unchanged, and exacerbation) at the end of 1999, by a logistic regression procedure.6 The probability of exacerbation, unchanged, or alleviation with the respective treatment modality was evaluated in relation to the probability of treatment effectiveness of each modality, with HD-RM serving as the reference. In the evaluation, exacerbation, unchanged, and alleviation, which were the responses to the questionnaire, were assigned tentatively numerical values in that order (ie, 0, 1, and 2), so as to determine the effect of each treatment modality in relation to the effect of HD-RM as “the risk of worse therapeutic effect.” The lower the numerical value was, the greater the risk of a worse therapeutic effect. In analyzing the association between each of the treatment methods and the risk of worse therapeutic effect, the risk was adjusted mathematically by the basic background factors of sex, age, duration on dialysis therapy, and Kt/V for urea.

Subjects for Analysis For analysis, we selected 1,196 patients meeting the following criteria: patients whose kidney disease was diabetic nephropathy, patients on thrice-weekly hemodialysis as of the end of 1998, patients who did not still suffer from DRA as of the end of 1998, patients who replied they already had DRA as of the end of 1999, and patients on dialysis Table 1.

Background of Subjects

Total no. Sex Male Female Primary disease DM Non-DM Age (y) Duration on dialysis (y) Kt/V for urea

1,196 672 524 0 1,196 59.2 (⫾12.1)* 10.9 (⫾6.3)* 1.44 (⫾0.3)* Effectiveness

Treatment Modality

HD using regular membrane HD using high-flux membrane HD with ␤2-microglobulin adsorption column Off-line HDF On-line HDF Original push/pull HDF Total

Exacerbation

Unchanged

Alleviation

30 74 1 7 0 0

232 665 5 35 2 1

3 100 6 28 5 2

265 839 12 70 7 3

112

940

144

1,196

Abbreviations: DM, diabetes mellitus; HD, hemodialysis; HDF, hemodiafiltration. *Values are mean (⫾SD).

Total

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Patients were divided into several groups according to age, duration on dialysis, or Kt/V for urea, as follows: Age (five groups), more than age 0 to less than age 30, more than 30 to less than 45, more than 45 to less than 60, more than 60 to less than 75, and more than 75 years; duration on dialysis (six groups), more than 2 years to less than 5 years, more than 5 to less than 10 years, more than 10 to less than 15 years, more than 15 to less than 20 years, more than 20 to less than 25 years, and 25 years or more; and Kt/V for urea (seven groups), less than 0.8, 0.8 to less than 1.0, 1.0 to less than 1.2, 1.2 to less than 1.4, 1.4 to less than 1.6, 1.6 to less than 1.8, and 1.8 and higher. As mentioned earlier, among 1,196 patients finally selected for analysis, only 7 patients were on on-line HDF, and only 3 were on push/pull HDF treatment. Because so few patients were treated by a possibly effective modality (ie, on-line HDF and push/pull HDF), a multivariate analysis, such as logistic regression analysis, may not be suited to the analysis of the association between “the risk of worse therapeutic effect” and a therapeutic modality. For this reason, before conducting the logistic regression analysis, we compared the effects of each treatment modality with that of the HD-RM group using Fisher’s exact test.7 Then, when a treatment modality showed a statistically significant difference with the HD-RM group, we made this modality the subject of a logistic regression analysis.

RESULTS

Fisher’s Exact Test Comparison of the patient group treated by on-line HDF with that by HD-RM revealed a statistically significant difference in therapeutic effect between the two groups (P ⬍ 0.001). This difference was also true of the patient group on push/pull HDF when compared with the HD-RM group (P ⬍ 0.001). Based on these analytical results, patients on either on-line HDF or push/ pull HDF were included among the subjects of the logistic regression analysis. Logistic Regression Analysis Sex, age, duration on dialysis. No significant association was found between the risk of worse therapeutic effect and sex or age (Table 2). This risk tended to be higher, however, as the duration on dialysis was longer. The risk in patients on dialysis for more than 20 to less than 25 years was statistically significantly higher than for patients on dialysis for more than 5 but less than 10 years. Kt/V for urea. The risk of worse therapeutic effect was higher for a patient with a low Kt/V for urea and lower for a patient with a high Kt/V for urea. Nevertheless, the difference did not reach statistical significance.

Hemopurification. On-line HDF, O-PPHDF, and off-line HDF treatment modalities showed a low risk of worse therapeutic effect. The simplest form of therapy used for DRA, HD-HFM, showed a 0.424 times lower (statistically significant) risk than in patients undergoing HD-RM. DISCUSSION

In DRA, amyloid fibrils are known to originate in ␤2-microgloblin with a molecular weight of 12,000 d, which accumulates in the body in renal failure.2 The efficient removal of lowmolecular-weight proteins such as ␤2-microgloblin is considered effective for treatment and prevention of DRA onset. Modalities available for this kind of treatment include HD-HFM, various types of hemodiafiltration, HD-␤2MAC, and HDF-␤2MAC. In the present analysis, on-line HDF and O-PPHDF presented the lowest risk of worse therapeutic effect in terms of DRA, followed by HD-␤2MAC and off-line HDF. Because no commercially available bottled biofluid is needed as the replacement fluid in on-line HDF and O-PPHDF, much more replacement of the body fluid is possible with these treatment modalities than with regular off-line HDF. For this reason, the ␤2-microglobulin removal rate is higher with on-line HDF and O-PPHDF than with off-line HDF. The lower risk of worse therapeutic effect (ie, higher therapeutic effectiveness) of on-line HDF and push/ pull HDF for DRA in the present study could be due to their greater removal of low-molecularweight proteins. HD-␤2MAC has been reported to be effective in mitigating DRA symptoms.8 In the present analysis, HD-␤2MAC showed a low risk of worse therapeutic effect (ie, higher therapeutic effectiveness) followed by on-line HDF and O-PPHDF, corroborating earlier reports. Off-line HDF, followed by on-line HDF and HD-␤2MAC, displayed lower risk of worse therapeutic effect than HD-HFM. These findings suggest that even if the body fluid replacement volume was less with off-line HDF than with on-line HDF and push/pull HDF, the therapeutic effectiveness still is greater with off-line HDF than with hemodialysis with little body fluid replacement. A HDF approach of whatever type has greater effectiveness in treating DRA than hemodialysis.

OUTCOMES OF HEMODIAFILTRATION Table 2.

S215 Risk Factors of Worse Therapeutic Effect

Risk Factors

Sex Male Female Age (y) 0ⱕ⬍30 30ⱕ⬍45 45ⱕ⬍60 60ⱕ⬍75 ⱕ75 Duration on dialysis (y) 2ⱕ⬍5 5ⱕ⬍10 10ⱕ⬍15 15ⱕ⬍20 20ⱕ⬍25 25ⱕ Kt/V for urea ⬍0.8 0.8ⱕ⬍1.0 1.0ⱕ⬍1.2 1.2ⱕ⬍1.4 1.4ⱕ⬍1.6 1.6ⱕ⬍1.8 1.8ⱕ Treatment modality HD using regular membrane HD using high-flux membrane Off-line HDF On-line HDF Original push/pull HDF HD with ␤2-microglobulin adsorption column

Relative Risk (95% Confidence Limits)

P Value

1.000 (Reference) 1.104 (0.807-1.509)

Reference ns

1.665 (0.412-6.722) 0.719 (0.441-1.175) 1.000 (Reference) 1.002 (0.732-1.371) 1.098 (0.675-1.788)

ns ns Reference ns ns

0.846 (0.560-1.277) 1.000 (Reference) 1.277 (0.863-1.890) 1.330 (0.869-2.036) 2.690 (1.602-4.519) 1.519 (0.477-4.839)

ns Reference ns ns 0.0002 ns

3.134 (0.560-17.52) 1.743 (0.751-4.047) 1.000 (Reference) 0.811 (0.518-1.268) 0.852 (0.538-1.347) 0.641 (0.387-1.063) 0.607 (0.332-1.110)

ns ns Reference ns ns ns ns

1.000 (Reference) 0.489 (0.349-0.685) 0.117 (0.061-0.224) 0.013 (0.002-0.081) 0.017 (0.001-0.276) 0.054 (0.013-0.221)

Reference 0.0001 0.0001 0.0001 0.0041 0.0001

Abbreviations: HD, hemodialysis; HDF, hemodiafiltration; ns, not significant.

The “risk of worse therapeutic effect” for a patient on HD-HFM treatment, although higher than for patients on the above-mentioned HDF modalities, is less than for HD-RM. These results show that even in dialysis treatment with little body fluid replacement a certain level of DRA improvement can be expected as long as the switch is made to a dialyzer with higher performance in eliminating low-molecular-weight protein. The earlier reports of improvement of patients with DRA by HD-HFM treatment9 are supported by the present findings. The results determined by the present analysis appear to show that any method with highefficiency removal of ␤2-microglobulin and other low-molecular-weight proteins is associated with improvement in patients with DRA. The predialysis serum ␤2-microglobulin concentration was

compared for each of the therapeutic modalities used with the patients under study here, but no statistically significant differences were found (data not shown). One cannot deny the possibility that some factor other than a high rate of low-molecular-weight protein removal might play a role in the association established between the improvement in DRA patients and the various HDF methods in the present study. Among 1,196 finally selected patients for analysis, only 7 patients were on on-line HDF and only 3 were on push/pull HDF treatment. Fisher’s exact test can show the presence or absence of a bias in patient distribution among fewer than 10 patients. In the investigation, Fisher’s exact test showed that these two modalities had a significantly better treatment than HD-RM did. The result should not be ignored.

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In the present investigation, the patients treated by different types of HDF or HD-␤2MAC accounted for only 8% (92 patients) of the overall patient group compared with 70% of the group (839 patients) on HD-HFM. Patients on HD-RM (265 patients), which promises virtually no highefficiency removal of low-molecular-weight protein, accounted for 22% of the total. These findings suggest that among patients in Japan suffering from DRA complications, only a few are treated with a modality of proven effectiveness for DRA and that many of these patients are under treatment with a modality not sufficiently effective against DRA. Based on the results of this study, any type of HDF should be used extensively for patients with DRA. REFERENCES 1. Nakai S, Shinzato T, Sanaka T, Kikuchi K, Kitaoka T, Shinoda T, Yamazaki T, Sakai R, Omori H, Morita O, Iseki K, Kubo K, Tabei K, Masakane I, Fushimi K, Akiba T: An overview of dialysis treatment in Japan (as of Dec. 31, 1999). J Jpn Soc Dial Ther 34:1-31, 2001 2. Gejyo F, Yamada T, Odani S, Nakagawa Y, Arakawa M, Kunitomo T, Kataoka H, Suzuki M, Hirasawa Y, Shirahama T: A new form of amyloid protein associated with

chronic hemodialysis was identified as beta 2 microglobulin. Biochem Biophys Res Commun 129:701-706, 1985 3. Lornoy W, Becaus I, Billiouw JM, Sierens L, Van Malderen P, D’Haenens P: On-line haemodiafiltration: Remarkable removal of beta2-microglobulin: Long-term clinical observations. Nephrol Dial Transplant 15:S49-S54, 2000 (suppl 1) 4. Locatelli F, Mastrangelo F, Redaelli B, Ronco C, Marcelli D, La Greca G, Orlandini G: Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters. The Italian Cooperative Dialysis Study Group. Kidney Int 50:1293-1302, 1996 5. Patient Registration Committee Headquarters of the Japanese Society for Dialysis Therapy: An overview of dialysis treatment in Japan (as of Dec. 31, 1998). J Jpn Soc Dial Ther 33:1-27, 2000 6. SAS Institute Inc: The Logist procedure, in: SAS/ STAT User’s Guide, Version 6 (ed 4), Volume 2. Cary, NC, SAS Institute Inc, 1989, pp 1071-1126 7. Mehta CR, Patel NR: A network algorithm for performing Fisher’s exact test in rxc contingency tables. J Am Statist Assoc 78:427-434, 1983 8. Furuyoshi S, Nakatani M, Taman J, Kutsuki H, Takata S, Tani N: New adsorption column (Lixelle) to eliminate beta2-microglobulin for direct hemoperfusion. Ther Apheresis 2:13-17, 1998 9. 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 52:1096-1101, 1997