No abstract

Background: Residual kidney function (RKF) has consistently been a predictor of greater survival in maintenance hemodialysis (MHD) patients. The relationship between hemodialysis (HD) treatment frequency and RKF preservation has not been well examined. We hypothesized that initial twice-weekly HD helps in maintaining a longer RKF. Methods: In a dialysis center in Shanghai, 168 ESRD patients were screened and finally 85 patients were identified for this main cohort study. We first examined these 85 MHD patients; 30 of them were initiated with twice-weekly HD for 6 months or longer and 55 patients were started and maintained on thrice-weekly HD treatment. Then a subcohort study in 48 incident MHD patients was implemented to assess the independent risk factors responsible for RKF decline during the first year of HD therapy. Multivariate logistic regression analysis was then employed to examine the odds ratio of RKF loss. Results: The main cohort study showed that the clinical outcomes were almost the same between the two groups in 85 patients, but the percent of patients with RKF loss was significantly lower in the twice-weekly group compared with the thrice-weekly group, especially during the first year of HD initiation. In the 48 incident MHD patients, we found no significant differences between the two groups except for variations in the HD frequency, weekly Kt/V. The multivariate analysis showed that factors such as the male gender, HD frequency, URR and intradialytic hypotension episode were associated with RKF loss, and the odds ratio of RKF loss for each additional HD treatment per week was 7.2. Conclusion: Twice-weekly HD during the first year of dialysis therapy appears to be associated with better RKF preservation.

The μ-conotoxin μ-KIIIA, from Conus kinoshitai, blocks mammalian neuronal voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. We have determined its solution structure using NMR spectroscopy. Key residues identified previously as being important for activity against VGSCs (Lys7, Trp8, Arg10, Asp11, His12 and Arg14) all reside on an α-helix with the exception of Arg14. To further probe structure-activity relationships of this toxin against VGSC subtypes, we have characterised the analogue μ-KIIIA[C1A,C9A], in which the Cys residues involved in one of the three disulfides in μ-KIIIA were replaced with Ala. Its structure is quite similar to that of μ-KIIIA, indicating that the Cys1-Cys9 disulfide bond could be removed without any significant distortion of the α-helix bearing the key residues. Consistent with this, μ-KIIIA[C1A,C9A] retained activity against VGSCs, with its rank order of potency being essentially the same as that of μ-KIIIA, namely, NaV1.2 > NaV1.4 > NaV1.7 ≥ NaV1.1 > NaV1.3 > NaV1.5. Kinetics of block were obtained for NaV1.2, NaV1.4 and NaV1.7, and in each case both kon and koff values of μ-KIIIA[C1A,C9A] were larger than those of μ-KIIIA. Our results show that the key residues for VGSC binding lie mostly on an α-helix and that the first disulfide bond can be removed without significantly affecting the structure of this helix, although the modification accelerates the on- and off-rates of the peptide against all tested VGSC subtypes. These findings lay the groundwork for the design of minimized peptides and helical mimetics as novel analgesics.