Title:
Dialyser biocompatibility and flux characteristics do not influence dimethylarginine levels in chronic hemodialysis patients

Muriel Grooteman¹ ;Muriel Grooteman¹ ;Muriel Grooteman² ;Muriel Grooteman³ ;Muriel Grooteman¹ ;Muriel Grooteman¹

1. Vrije Universiteit Medical Center ; 2. Medical Center Alkmaar ; 3. Vrije Universiteit Medical Center

E-mail address corresponding author:
mpc.grooteman@vumc.nl

Background:
Cardiovascular disease is the major cause of morbidity and mortality in chronic hemodialysis (HD) patients. Asymmetric dimethylarginine (ADMA, molecular weight MW 202 D) levels are increased in HD patients, and independently predict mortality and cardiovascular events in this patient group. ADMA competitively inhibits NO synthase, thus decreasing NO availability. ADMA, but also symmetric dimethylarginine (SDMA, MW 202 D), share a common pathway with arginine (MW 174 D, substrate for NO) for entry into the cell. Although ADMA, SDMA and arginine are small molecules, reports on the effect of HD on these compounds are contradictory.

Methods:
15 Stable HD patients were dialysed during 4 weeks with 4 different dialysers in a cross-over design: low flux polysulfon (lfPS), low flux cuprammonium (lfCU), high flux PS (hfPS) and super flux polyethersulfon (sfPES) in random order. To exclude carry over effects, a washout of 2 weeks lfPS was instituted between each treatment period. Blood samples were drawn pre-dialysis before each period (baseline), as well as before (t0) and directly after (t4h) the last HD session of the 4th week on each membrane for the assessment of ADMA, SDMA and arginine. In order to confirm the experimental model, the complement activation product C3a (after 10 min of HD) and beta-2-microglobulin (ß2m) were determined.

Results:
Mean baseline levels of ADMA, SDMA and arginine were comparable at baseline in the different study periods. After 4 weeks of HD on each membrane, the levels remained stable before HD. During HD on each membrane, ADMA levels decreased 32% (0.62 to 0.43 µmol/l), whereas SDMA levels declined 44% (2.55 to 1.42 µmol/l). This decrease was observed in all patients. Mean arginine levels decreased as well (68 to 57 µmol/l), but only significantly with the high- and super flux membranes. After pooling all data (except for baseline values), the levels of ADMA, SDMA and arginine appeared to be dependent on the individual patient (and hence: patient characteristics) and time (before or after HD), rather than on the type of dialyser. ANOVA: explained variation between different patients ADMA 39%, SDMA 26%, arginine 52%, effect of patient on all values p<0.001; variation between time points for ADMA 48%, SDMA 55% and arginine 7%, p<0.001; an effect of the dialyser was not observed (<0.7%, p=0.9). As expected, C3a levels increased significantly more with CU as compared with the PS/PES dialysers (PES/PS from 346 ± 127 to 656 ± 237 ng/ml; CU from 299 ± 139 to 1206 ± 908 ng/ml, p<0.01;). Furthermore, after 4 weeks of HD on sfPES and hfPS, β2m decreased significantly (sf PES from 32 ± 10 to 26 ± 5 µg/l: p=0.001; hf PS from 32 ± 13 to 26 ± 7 µg/l; p=0.042), whereas it remained stable after 4 weeks of HD with the low flux dialysers.

Conclusion:
In conclusion, during HD with both biocompatible lfPS, hfPS and sfPES, and with bio-incompatible lfCU, ADMA and SDMA levels decreased markedly. At the same time, arginine levels declined as well, but not in all patients. After 4 weeks of HD with the different membranes, the levels of these compounds remained stable. Hence, although AMDA, SDMA and to a lesser extent arginine are cleared during HD, the levels of dimethylarginines and arginine seem to be far more dependent on patient-related factors than on the type of dialyser, regardless of its biocompatibility and flux characteristics. The nature of these patient-related factors remains to be investigated.

Subject:
Hemodialysis

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