Preparation And Characteristics Of Novel Blood Purification Adsorbent Towards Protein Bound Uremia Toxins

Protein bound uremia toxins(PBUT)broadly exist in patients with renal failure.As a class of toxins with molecular weight below 500 Dalton that bind to human serum albumin(HSA),PBUT accounts for about 26%of the toxins in patients with kidney failure.Indoxyl-sulfate(IS)and para-cresol sulfate(PCS)are typical PBUTs which have been proved to induce cardiovascular and cerebrovascular diseases for patients with renal failure.Blood purification has been used to treat patients with renal failure by removing water soluble small molecules such as creatinine and urea effectively.However,the clearance of PBUTs by blood purification is not sufficient and leaves the development of a highly efficient PBUT removal technique for patients with renal failure a vital task.As summarized below,efforts have been put into the design of water soluble absorbent and novel solid adsorbents by the author to offer new ways to remove PBUTs from patients with renal failure.Firstly,water soluble adsorbent,poly-β-cyclodextrin was synthesized by crosslinking βcyclodextrin with epichlorohydrin.When introduced into the dialysate during dialysis,poly-βcyclodextrin adsorbed indoxyl-sulfate efficiently:the adsorption equilibrium was reached in 30 min,and the capacity of poly-β-cyclodextrin to indoxyl-sulfate was 45 mg·g-1.Furthermore,the removal rate of indoxyl-sulfate by 2%(w/w)poly-cyclodextrin in the dialysate achieved 41%,which is significantly higher than that achieved by traditional therapy(20%).To evaluate the effects of the cavity size of cyclodextrin on the removal rate of PBUTs by poly-cyclodextrin,poly-α-cyclodextrin,poly-β-cyclodextrin,and poly-y-cyclodextrin were synthesized respectively.PCS with low clinical removal rate was taken as a model PBUT.All poly-cyclodextrins adsorbed PCS,while poly-β-cyclodextrin showed the highest removal rate among the adsorbents with a capacity of 123.5 mg·g-1.And the removal rate of PCS by poly-βcyclodextrin(0.5%w/w)in dialysis reached 96%in a single run.In the simulated blood,the removal rates of PCS.hippuric acid,quinolinic acid using poly-β-cyclodextrin(0.5%w/w)were 96%,98%,and 97%respectively,indicating the capability of poly-β-cyclodextrin to remove a broad spectrum of PBUTs.Although poly-β-cyclodextrin efficiently removed PBUTs,the risk of leaking poly-βcyclodextrin into blood caused by the broad range of pore sizes of the dialysis membrane limited its use in clinic.Novel solid PBUT adsorbents were designed accordingly.Secondly,the use of hollow carbonized pollen in the removal of PBUTs was evaluated.After carbonization,the specific surface area of carbonized pollen was 703 m2g-1,which is 1.56 times that of traditional active carbon.The capacity of carbonized pollen to PCS was 260 mg·g1.The removal rate of PCS was 81%by 0.5%(w/w)carbonated pollen from 0.2 mg·ml-1 PCS solution and dropped to 62%when 4%BSA was added in the PCS solution.After increasing the concentration of carbonized pollen to 2%,the PCS removal rate grew to 81%,which was significant higher than that of traditional active carbon(66%).Despite the high specific surface area of carbonized pollen,the irregular backbones and the lack of strength limited its further use.Covalent organic frame polymer adsorbent was then designed to solve the shortcomings.Finally,covalent organic frame polymer adsorbent(TC-Glu)was synthesized by reacting terephthaloyl chloride with glucose.With pore diameter of 6.1x5.6 A and specific surface area 136 m2·g-1,TC-Glu was capable of adsorbing hydrophobic molecules with molecular weight below 656 Dalton in a size-dependent manner.The obtained TC-Glu was also hydrophilic and hemocompatible,indicated by the low(9.2 mg·g-1)nonselective protein adsorption from plasma.Capacity of TC-Glu to PCS was 160 mg·g-1,and in 0.2 mg·ml-1 PCS solution with 4%BSA,0.5%,2%,and 4%(w/w)TC-Glu exhibited PCS binding rate of 83%,92%,and 96%,outperforming the carbonized pollen.Taken together,three novel PBUT adsorbents were synthesized in this paper.As all three differently designed adsorbents effectively removed protein bound PCS and IS,this work opens new avenue for the use of solid adsorbents in removing PBUTs by blood purification.