Bergner, A.

Lang, Susanne M.

Schiffl, Helmut

English

Universität München: Elektronischen Publikationen

Ultrapure dialysate reduces dose of recombinant human erythropoietin

H. Schiffl

S.M. Lang

A. Bergner

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Ultrapure Dialysate Reduces Dose of Recombinant Human Erythropoietin

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Letter to the EditorNephron 1999;83:278–279Ultrapure Dialysate Reduces Dose ofRecombinant Human ErythropoietinH. Schiffl S.M. Lang A. BergnerMedizinische Klinik, Klinikum Innenstadt, Universität München, DeutschlandHelmut Schiffl, MDMedizinische Klinik, Klinikum InnenstadtUniversität MünchenZiemssenstrasse 1D–80336 München (Germany)ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 1999 S. Karger AG, Basel0028–2766/99/0833–0278$17.50/0Accessible online at:http://BioMedNet.com/kargerDear Sir,The widespread availability of recombi-nant human erythropoietin (rHU-EPO) isone of the greatest advances in clinical neph-rology. Approximately 90–95% of dialysispatients treated with rHu-EPO respond withan improvement in their anemia, but indi-vidual doses may vary considerably. Themost important factors causing this varia-tion are acute or chronic inflammatory pro-cesses which may lead to marked resistanceto rHu-EPO. It is a well-known fact thatexposure of patient’s blood to even mildlycontaminated dialysate contributes to thesystemic inflammatory syndrome of uremiaby induction of cytokine synthesis [1]. How-ever, there are no data indicating whetherdifferences in the microbiological quality ofthe dialysate may affect the response to rHu-EPO in patients receiving regular hemodial-ysis.The aim of our prospective cross-overinvestigation was to compare the effect ofpotentially contaminated, commercial (un-filtered) and online produced, ultrapure dial-ysate on rHu-EPO doses. Twenty-four stableanuric dialysis patients gave informed con-sent to participate in the study which wasapproved by the local ethics committee.They all had normocytic normo-chromicanemia of end-stage renal disease and nor-mal levels of folic acid, vitamin B12 andferritin. None of the patients had acute orchronic infection, inflammatory disease,malignancy or chronic bleeding disorders orused immunosuppressive drugs or angioten-sin-converting enzyme inhibitors. Hemodi-alysis was performed with volumetricallycontrolled ultrafiltration (MTS 4008, Frese-nius, Bad Homburg, Germany) and biocom-patible high-flux dialyzers (Polysulfone, F60Fresenius, Bad Homburg, Germany). Thebicarbonate dialysate was either commercialor ultrafiltrated using polysulfone filters.Each treatment session lasted 3–5 h, withblood flow rates between 250 and 350 ml/min, and dialysate flow rates at 500 ml/min.Twelve patients each were randomly as-signed to treatment with unfiltered (com-mercial) dialysate for 3 months and crossedover to ultrafiltrated dialysate for another 3months or were treated in the reverse order.The microbiological quality of the dialysatewas checked monthly. Plasma C-reactiveprotein (CRP) levels and circulating inter-leukin-6 concentrations were measured byhighly sensitive enzyme-linked immunosor-bent assays.There were no statistically significant dif-ferences in the demographic characteristicsor treatment-associated parameters betweenthe 2 study groups at recruitment. Bothgroups had comparable target hemoglobinconcentrations and rHu-EPO doses (ß-epoie-tin, Boehringer, Mannheim, Germany) atthe start of the study (table 1).In group I continuation of commercialunfiltered dialysate (median 140, range 60–400 CFU) did not result in a significantchange of hemoglobin levels (10.2 B 0.2 g/dl), rHu-Epo doses (90 B 50 U/kg/week) orinflammation as determined by CRP (1.1 B0.2 mg/ml) or plasma IL-6 (55 B 15 pg/ml).The change of the dialysate after 3 months,however, caused a significant reduction inrHu-EPO doses (60 B 31 U/kg/week, p !0.05) despite comparable hemoglobin levels(10.3 B 0.3 g/dl) and furthermore led to asignificant fall in CRP (0.6 B 0.2 mg/dl, p !0.05) and IL-6 (35 B 10 pg/ml, p ! 0.05).In group II change of the unfiltered toultrapure dialysate caused a significant re-duction in rHu-EPO doses (62 B 32 U/kg/week, p ! 0.05) despite comparable hemo-globin levels (10.1 B 0.2 g/dl) and a signifi-cant fall in CRP and IL-6 concentrations wasobserved (0.7 B 0.2 mg/dl and 38 B 14 pg/dl, p ! 0.05. Reinstitution of commercialdialysate (median 120, range 40–400 CFU)resulted in increased rHu-EPO doses (87 B45 U/kg/week) to stabilize hemoglobin con-centrations at comparable levels (10.2 B0.3 g/dl) and led to an intensified systemicinflammatory response as marked by risesUltrapure Dialysate and Erythropoietin Nephron 1999;83:278–279 279Table 1. Patient characteristics at recruitment (mean B SD)Group I Group IINumber of patients 12 12Age, years 58B14 61B13Gender, male/female 6/6 6/6Time on dialysis, months 45B14 48B18Weight, kg 72B16 76B13Parathyroid hormone, pg/ml 133B15 121B36Serum aluminium, Ìg/l 20B15 25B20KT/V urea 1.3B0.3 1.4B0.2Hemoglobin, g/dl 10.2B0.5 10.1B0.4rHu-EPO, U/kg/week 92.5B52.5 85.7B46.8CRP, mg/dl 1.2B0.2 1.4B0.4IL-6, pg/ml 58B23 52B18Table 2. Effects of commercial vs. ultrapure dialysate on rHu-EPOdoses (mean B SD)CommercialdialysateUltrapuredialysateNumber of patients 24 24Hemoglobin, g/dl 10.2B0.3 10.2B0.3rHu-EPO, U/kg/week 87B44 61B30** p ! 0.05 vs. corresponding value of commercial dialysate.in CRP (1.3 B 0.2 mg/dl) and IL-6 (61 B16 pg/dl; table 2).These data demonstrate that even mildlycontaminated commercial bicarbonate dial-ysate causes chronic inflammation by induc-tion of cytokine synthesis. Use of ultrapure(filtered, pyrogen-free and sterile) dialysatereduced the rHu-EPO doses required tomaintain hemoglobin levels via a reductionin systemic inflammatory processes (ta-ble 2).The mechanisms underlying the in-creased need for rHu-Epo doses in patientstreated with commercial dialysates may in-clude suppression of endogenous erythropoi-etin secretion, iron delivery and prolifera-tion of erythrocyte precursors [2]. Recombi-nant erythropoietin administration providesa number of undisputed benefits to patientsundergoing maintenance dialysis, but addssignificantly to the costs of hemodialysistreatment. Thus, efforts should be directedat minimizing the dose of rHu-EPO toachieve optimal target hemoglobin concen-trations. The use of ultrapure bicarbonatedialysate is inexpensive and undoubtedlyhas clinical implications for the treatment ofanemia of chronic renal failure.References1 Schindler R, Lonnemann G, Schäffer J, Shal-don S, Koch K-M, Krautzig S: The effect ofultrafiltrated dialysate on the cellular contentof interleukin-a receptor antagonist in patientson chronic hemodialysis. Nephron 1994;68:229–233.2 Goicoechea M, Martin J, DeSequera P, Quiro-ga JA, Ortiz A, Carreno V, Caramelo C: Role ofcytokines in the response to erythropoietin inhemodialysis patients. Kidney Int 1998;54:1337–1343.

Caramelo C: Role of cytokines in the response to erythropoietin in hemodialysis patients. Kidney Int 1998;54:

Krautzig S: The effect of ultrafiltrated dialysate on the cellular content of interleukin-a receptor antagonist in patients on chronic hemodialysis.

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Ultrapure dialysate reduces dose of recombinant human erythropoietin

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