Effect of Replacement Volume of Haemodiafiltration and AST-120 on Toxins, Oxidative Stress and MicroInflammation
Condition: Loss of Solute Clearance
Study type: Interventional
Phase: Phase 4

Summary: 
      Accumulating evidence suggested that increased oxidative stress (OxSt) as well as
      inflammation are risk factors for cardiovascular events in hemodialysis patients. The
      incremental effect of online haemodiafiltration (OL-HDF) on markers of microinflammation ,and
      OxSt is less clear. Besides, the relationship between protein-bind uremic toxin and
      microinflammation remains obscure. The aim of this study was to evaluate the effect volume
      replacement of on-line hemodiafiltration on proinflammatory peripheral monocytes (percentage
      of CD14+CD16+ cells), PAF, IL-6 and on the plasma level of several oxidative stress markers
      as well as several protein-bound uremic toxins such as p-cresol, indole sulfate etc. In a
      case controlled study, 30 patients on OL-HDF will be evaluated. The association between
      protein-bound uremic toxins such as p-cresol, indole sulfate etc and AST-120, a spherical
      adsorptive carbon preparation (Kremezin) will also being investigated.
    

Detailed description: 
      Background

      High convection volume OL-HDF techniques constitute progress towards renal replacement
      therapy which is most similar to the native kidney. These techniques offer a higher clearance
      of uremic substances with a greater range of molecular sizes, they require the use of
      biocompatible membranes and ultrapure dialysis fluid, which has been associated with
      additional clinical benefits. The superiority of OL-HDF to HD has been suggested by the
      results of several studies . Solute removal capacity of uremic toxins is enhanced by huge
      volume substitution with OL-HDF . Most clinical studies agree that OL-HDF permits a similar
      or slight larger reduction rate of small solutes per session as that of HD: 70-80% for urea
      (60 daltons (da) . Using b2M as a solute marker of larger uremic toxins, it has been shown in
      a controlled study that the reduction ratio of b2M per session was 20-30% higher with OL-HDF
      than with high-flux HD (72.7 versus 49.7%), and that regular use of OL-HDF significantly
      reduces circulating levels of predialysis b2M (median value 20 mg/l) It has also been shown
      that OL-HDF can remove larger solutes such as myoglobin (16 kDa) and retinol-binding protein
      (25 kDa).The capacity to remove middle-sized peptide substances is positively correlated to
      the convective clearance and the amount of fluid exchanged per session, and it is the
      enhanced convective clearance achieved by OL-HDF that is the primary mechanism for removing
      larger uremic solutes. It has also been shown that OL-HDF reduces the circulating levels of
      advanced glycation end products that are putatively implied in the dialysis-related
      complications of long-term dialysis patients Recently, one large observational cohort study
      with robust adjustments for demographic and comorbid confounding factors showed an
      association with lower mortality risk for OL-HDF. In their study, they found that the OL-HDF
      group receiving the higher fluid volume exchange (> 15 l per session) had a significantly and
      substantially lowered risk of death (RR=0.65, P=0.01) .A large number of retained larger
      solutes and protein-bound compounds are involved in uremic toxicity. Among them such as
      p-cresol and indole sulfate etc, which seem to be related to deleterious biological and
      clinical effects but are difficult to remove by dialysis. Particularly, protein-bound toxins
      represent a challenge for extracorporeal renal replacement strategies because only the
      unbound, mostly low-molecular solute can pass current dialysis membranes while the bound
      fraction is retained. p-cresol and indoxyl sulfate (IS) are among the most frequently studied
      protein-bound toxins in patients with end-stage renal disease. . Similar to other
      protein-bound compounds, p-cresyl sulfate(PCS) is poorly removed by hemodialysis because of
      its protein binding and its high ratio of distribution volume to clearance . Compared with
      low-flux, high-flux dialysis membranes generally do not enhance the elimination of
      protein-bound toxins, while albumin-leaking super-flux membranes are superior especially in
      removing indoxyl sulfate (IS). One previous study suggested that some protein-bound solutes
      (p-cresol) may be more efficiently removed by high-efficiency HDF than by highflux HD while
      discrepant result was suggested by one recent study .Uraemic toxins accumulate and lead to
      uraemic syndrome as the glomerular filtration rate declines. Earlier studies, including the
      Hemodialysis (HEMO) trial and the Adequacy of Dialysis Mexico (ADMEX) trial, showed that
      increasing the removal of water-soluble solutes above the current target did not reduce
      mortality in dialysis patients. This finding indicates that uremic solutes, other than small
      water-soluble molecules, may play a role in patient outcome. Some recent studies suggested
      that in non-diabetics on hemodialysis, the free p-cresol serum concentration is significantly
      associated with cardiovascular disease and may help to predict overall mortality in this
      patient group. The interrelation of p-cresyl sulfate (PCS), the main in vivo metabolite of
      p-cresol, with vascular disease in uremia may be derived from its pro-inflammatory effect on
      unstimulated leucocytes leading to oxidative stress and, consequently, atherosclerosis . An
      in vitro study revealed that p-cresol also depresses the respiratory burst activity of
      phagocytes, inhibits plate- let-activating factor synthesis and reduces endothelial cell
      response to inflammatory cytokines. Further evidence has indicated that p-cresol plays a
      major role in endothelial dysfunction, which is a characteristic of uremic syndrome.
      Similarly, IS may have a significant role in the vascular disease and higher mortality
      observed in CKD patients. Apart from some earlier studies that reported the toxic biologic
      effects of IS, it has been reported that IS (at similar concentrations as those found in CKD
      patients) is capable of inhibiting endothelial cell proliferation and thus impairing the
      endothelium self-healing ability . Yamamoto et al. showed that IS can stimulate the
      proliferation of rat vascular smooth muscular cells in vitro . Itwas subsequently
      demonstrated that IS induces aortic calcification in vivo in a rat model of hypertension,
      with aortic wall thickening and the expression of osteoblast-specific proteins .Since 1991,
      the carbonaceous adsorbent AST-120 has been available to treat patients with chronic kidney
      disease (CKD) in Japan. Nonetheless, in many countries it is not commonly used. In animal
      models of CKD, AST-120 removes uremic toxins and reduces oxidative. Years ago, Niwa et al had
      shown that AST-120 was effective in reducing the serum concentration of albumin-bound indoxyl
      sulphate in hemodialysis patients by adsorption of indole in the intestines, and that it
      relieved itching in hemodialysis patients with generalised pruritus . It is noteworthy that
      AST-120 which adsorbs hydro- phobic uremic toxins such as IS and attenuates the oxidative
      stress generated by the latter-has been shown to favorably influence CKD and the related
      cardiovascular outcomes in animal and clinical studies. Accordingly, in a CKD rat model in
      which oxidative stress was induced by adriamycin, Fujii et al. demonstrated that the rats
      treated with AST-120 had lower levels of IS, smaller heart and left ventricular volumes,
      cardiac fibrosis, and lower histologic expression and urinary excretion of oxidative stress
      markers than nontreated controls, despite having similar renal function. In line with these
      findings, it had been reported that AST-120 given to CKD patients before dialysis initiation
      improved their overall survival rates in comparison with CKD patients to whom AST-120 was not
      administered. Lastly, in a recent study in which AST-120 was administered to predialysis CKD
      patients for 2 yr, a significant reduction in the carotid intimamedia thickness and PWV was
      reported in the AST-120 group when compared with those not receiving AST-120 .In the present
      study, the investigators attempted to compare the effects of low and high replacement volumes
      on the removal of protein-bound toxins and LMW proteins in prevalent ESRD patients receiving
      online high-efficiency post-dilution hemodiafiltration. In addition, the investigators
      evaluate the effect of adsorptive measures, AST-120, on the inflammatory and oxidative status
      of dialysis patients.

      Research design and methods

      Patients 30 stable chronic dialysis patients receiving OL-HDF patients who had been treated
      for > 3 months will be included in this study. Only non-smoking patients without recent
      infections and without intake of antibiotics or immunosuppressive agents in the last 2 weeks
      before the study will be selected.

      Study design

      The study will be conducted as a case-control study. Stable chronic kidney disease stage 5
      patients on regular three times weekly maintenance dialysis were enrolled into the study
      after they had given written informed consent. The patient's concomitant medications were
      continued in an unchanged manner. Each patient underwent randomly one study week of three
      consecutive haemodiafiltration treatments with the polysulphone dialysis membrane.
      Haemodiafiltration were performed using Fresenius 4008 H monitors (Fresenius Medical Care,
      Bad Homburg, Germany). The ultrafiltration flow rate (QUF) of each session was set according
      to the individual patient's interdialytic weight gain. Anticoagulation was performed by
      unchanged adoption of the previous routine heparinization Treatment duration, QB and QD, as
      well as the infusion flow rate (QI) in post-dilution haemodiafiltration were kept constant
      for each patient for 3 months.At the silent of study, patients receiving OL-HDF were
      randomized into 2 arm,namely those with replacement volume ≦ 15 L & > 15 L.After 2 months,
      the replacement volume of the group with < 15 L replacement volumes will be increased to > 15
      L for another 2 months (Group A). Those with >15 L replacement volumes will be kept
      unchanged(Group B). After a further 2 months, patients in group A will be randomized to take
      AST-120 for 3 months as shown in Figure 1All samples blood will be collected during the
      midweek dialysis from the AV fistula, immediately after the insertion of the dialysis cannula
      but before the administration of heparin. Blood was collected before dialysis on 3 occasions
      namely month 0, 3 and 6 m. Blood before dialysis was drawn Blood was sampled in 4 cc Venoject
      II tubes and centrifuged (10 min, 3000 r.p.m.). Serum were immediately stored at -20°C until
      assayed.
    

Intervention name(s): Kremezin
Intervention type(s): Drug
Intervention description(s): Kremezin is an oral adsorbent, 9g/day in treatment arm
Other intervention name(s): AST-120
Intervention model: Single Group Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: AST-120; HDF; Replacement Volume described above