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Purpose: Dialysis morbidity results partly from middle and large molecule retention, which is poorly removed by conventional hemodialysis (HD). The potential benefit of convective treatments could be the enhanced toxin removal over a wide molecular weight spectrum. This study aimed to evaluate cystatin C (cis), beta2-microglobulin (beta2-m) and C-reactive protein (CRP) removal behavior during hemodiafiltration reinfusion vs conventional low-flux HD (1.8 m2 low-flux polysulphone) (bicarbonate dialysis (BD)). The molecular weights of the substances evaluated in this study were as follows: cis = 13,300 daltons, beta2-m = 11,818 daltons, CRP = 160,000 daltons., Methods: Twelve patients on stable HD (six males, six females), were enrolled; six patients underwent BD and six patients underwent HFR. We measured arteriovenous serum cis, beta2-m and CRP levels, in three consecutive mid-week sessions at the following periods: pre/post-dialysis and after 60 min from the beginning of the session. At 60, 120 and 180 min of HFR, we collected the ultrafiltrate for cis, beta2-m, and CRP evaluation., Results: Cis, beta2-m and CRP mean values did not differ at pre-dialysis in the two groups. Pre/post- dialysis difference for cis in HFR vs BD was statistically significant (p=0.002) because cis reduced in HFR and increased in BD during the session. Beta2-m and CRP pre/post- dialysis differences in HFR vs BD were not significant. Cis clearance, measured 60 min after the beginning of the session was 34.2 +/- 20.1 mL/min in HFR and 24.8 +/- 18.4 mL/min in BD (p<0.05). beta2-m and CRP clearances did not differ among the treatments. Regarding the ultrafitrate concentrations during the HFR session, cis significantly decreased (2.5 +/- 0.6 mg/dL at 60 min and 2.0 +/- 0.4 mg/dL at 180 min; p=0.004), as well as beta2-m (21.5 +/- 12.9 mg/dL and 19.0 +/- 14.1 mg/dL, respectively; p=0.02). Ultrafiltrate CRP values, as expected, did not differ during HFR., Conclusions: This study demonstrated that cis, a middle molecule, is well depurated in HFR, while in BD it increases. Beta2-m, although better removed in the convective phase during HFR, does not demonstrate a removal difference in HFR and in BD. CRP, a large molecule, does not have significant removal. Since cis and beta2-m have almost the same molecular weight, why do they have a different depuration? We need further studies to evaluate if membranes can remove these molecules or if protein electrical charges or their stereoscopy enables their removal.