Toxins Removal and Inflammatory State modulAtion During Online Hemodiafiltration: Comparison of Two Different Dialyzers

Inflammation Clinical Trial

— TRIAD2  

Official title:

Toxins Removal and Inflammatory State modulAtion During Online Hemodiafiltration: Comparison of Two Different Dialyzers

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04554498
• Other study ID #: 596/2019/Oss/AOUBo
• Status: Not yet recruiting
• Phase: N/A
• Start date: January 1, 2022
• Est. completion date: May 1, 2024

Study information

• Verified date: March 2021
• Source: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Contact: Gaetano La Manna
• Phone: +390512144577
• Email: gaetano.lamanna[@]unibo.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary goal of the study is to evaluate in patients on three times a week on-line HDF the efficacy, in terms of toxin removal and modulation of the inflammatory state, of two different dialyzers: Helixone versus Asimmetric cellulose triacetate (ATA).

Description:

Patients with end-stage renal disease (ESRD) have a significantly increased cardiovascular mortality rate compared to the general population.

According to the USRDS (United States Renal Data System), in 2017 the prevalence of cardiovascular disease in the United States was 65.8% in patients with chronic kidney disease (CKD), compared to 31.9% of the subjects with stable renal function (https://www.usrds.org/2017/view/v1_04.aspx).

In the natural history of nephropathy, besides the traditional cardiovascular risk factors, an increasingly important role is played by the nontraditional factors related to uremia and dialysis treatment, namely anemia, hyperhomocysteinemia, malnutrition, hyperparathyroidism, electrolyte imbalance, and above all chronic inflammatory state and oxidative stress. The main components of dialysis-related inflammatory response include neutrophil and monocyte activation, cytokine release, oxidative stress with production of free radicals, lipid and protein oxidation, and alterations in blood redox state.

There is much evidence to indicate that ESRD patients, especially those on dialysis, are exposed to increased oxidative and carbonyl stress, that cause chemical modifications of proteins and accumulation of AGEs (advanced glycation end products).

The formation of AGEs occurs through Maillard reaction, a non-enzymatic glycation of peptide amino groups, resulting in protein structural and functional alteration and production of reactive carbonyl species .

Several studies have demonstrated a correlation between the levels of tissue AGEs and the development of various complications, since the accumulation of AGEs constitutes an index of hyperglycemia, oxidative stress and inflammation. The activation and up-regulation of the AGE receptors, including the main one RAGE (AGE Receptor), leads to the initiation of inflammatory cascades involved in the formation of atherosclerotic plaques and endothelial dysfunction, and lastly in the pathogenesis of cardiovascular disease. AGEs are also related to the thickening of the intima-media tunica of the carotid arteries, considered a marker of arteriosclerosis, as clinically confirmed by the close relationship between coronary artery disease and atherosclerotic complications in diabetes and renal failure.

Besides AGEs, a huge pattern of protein-bound toxins and of middle molecular weight uremic toxins are known to contribute to the uremic syndrome in terms of cardiovascular complications, inflammation and fibrosis . Concerning protein-bound uremic toxins, p-cresyl sulfate and indoxyl sulfate have received considerable attention recently. Among middle molecules, B2M, free light chains and FGF23 have been identified as markers of disease progression and mortality in CKD and hemodialysis.

Furthermore, the activation of leukocytes, both in response to the exposure to dialysis membranes and as a consequence of the retrotransportation of substances that promote the expression of cytokines from the dialysate, increases the release of proinflammatory cytokines, such as IL-1β, TNF-α and IL-6.

The biocompatibility and flow properties of the different filters can influence the inflammatory and oxidative response to dialysis and the levels of oxidized molecules. In general, short-term dialysis with high-flow membranes has been shown to decrease plasma levels of oxidized low-density lipoproteins, regardless of the filter material.

Nonetheless, the introduction of high-flux membranes, which increased clearance of middle molecules, appears to be inadequate to improve patient survival, as reported by two major randomized trials, the HEMO study [24] and the MPO study.

The use of on-line HDF, that combines convective and diffusive solute removal, can counterbalance the rapid decrease of middle molecule diffusion obtained with high flux hemodialysis. The integration of diffusion with convection allows a more modest sieving coefficient decrease for middle molecular weight solutes. To date, evidence from four randomized controlled trials on HDF suggests, although not definitely, that HDF with convection volumes >20 L results in better patient outcomes .

Moreover, a correlation of the membrane typology with inflammation and oxidative stress in the medium-long term was found in patients undergoing chronic dialysis treatment. A prospective study in a cohort of 50 patients who started hemodialysis with a high-flux polysulfone membrane (HF80 series, Fresenius Medical Care, St. Wendel, Germany) evaluated the variation of the inflammation and oxidative stress biomarkers. The results showed significantly increased circulating levels of IL-6, C-reactive protein (CRP) and higher carbonylation rate in dialysis patients compared to healthy controls in the first year of observation, and this trend was maintained in the following 12 months.

Successive studies investigated the long-term effects on inflammation and oxidative stress of dialysis with Helixone (Fresenius Medical Care), another type of high-flux polysulfone membrane designed to maximize the clearance of uremic toxins of average molecular weight (> 500 Daltons, Da) compared to conventional high-flux membranes. The introduction of changes as reduced hollow fiber wall thickness (≈35 μm), smaller inner diameter (≈185 μm) and higher average pore size (≈3.3 nm) has improved the clearance of medium molecular weight molecules, including β2-microglobulin (B2M), limiting the passage of larger molecules like albumin, without significant effects on inflammatory parameters .

The features of synthetic membranes related their chemical composition and the asymmetric structure of the fibers make them preferable for new highly-convective therapies, such as high-volume hemodiafiltration (HDF), only partially allowed with cellulose.

However, cellulose triacetate (CTA) and modified cellulose membranes remain the best option for the patients with hypersensitivity reactions to synthetic fibers. Although synthetic membranes, including those based on polysulfone, have a lower risk of hypersensitization than non-biocompatible ones (such as Cuprophane), in some cases adverse reactions have been reported, plausibly due to the contact between the dialyzer itself with plasma proteins and platelets.

Moreover, the choice of polysulfone membranes has been proven to affect the intracellular and serum levels of bisphenol A (BPA, molecular weight 228.3 kDa), a ubiquitous environmental toxicant found in plastic food and beverage containers, as well as in some dialyzers, with several detrimental effects. BPA is considered an endocrine-disrupting chemical that acts mainly as a female hormone: it is associated with reproductive dysfunction, immune abnormality and increased incidence of cancer. Patients on hemodialysis are a high-risk population for BPA overload, because the normal urinary elimination of the conjugated molecule decreases with low renal function. For these reasons, BPA can be thought as a uremic toxin, similarly to p-cresol, and a particular attention should be given to BPA-containing medical devices, including dialysis membranes.

Mas et al. compared BPA-free and BPA-containing dialyzers in 72 patients under on-line HDF, using a prospective 9-month, crossover study design. BPA-free dialyzers determined a greater long-term decrease in BPA levels compared to BPA-containing dialyzers, although at three months the difference was not significant. This may be due to the use of the on-line HDF technique that has been related to lower BPA levels than conventional hemodialysis.

Recently, a new generation filter in asymmetric triacetate (ATA) has been introduced, born from a technology that combines the requirements of synthetic membranes for the possibility of being used with high-volume HDF and the advantages of natural fibers (cellulose) in terms of reduced allergic reactions.

These novel ATA membranes have been demonstrated to achieve satisfactory Kt and convection volume, with good biocompatibility and inflammatory profiles, indicating them as a valuable option for patients allergic to synthetic membranes under HDF treatment.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 16
• Est. completion date: May 1, 2024
• Est. primary completion date: May 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with chronic renal failure under periodic standard bicarbonate hemodialysis;

• Three times a week dialysis session;

• Residual diuresis <200 mL/day;

• Age >18 years;

• Vascular access for hemodialysis with blood flow >250 mL/minute;

• Need of on-line hemodiafiltration (HDF) for signs of middle molecules intoxication (e.g. B2M >30 mg/L, peripheral neuropathy, cardiovascular comorbidities) or for intradialytic hypotension.

Exclusion Criteria:

• Acute coronary syndrome;

• Acute hemorrage;

• Enrollment in another study protocol;

• Active infection;

• Malignancy;

• Inability to provide written signed consent to participate in the study.

Related Conditions & MeSH terms

• Hemodialysis Complication
• Inflammation
• Toxemia
• Uremic; Toxemia

Intervention

Device:
• 1) high flux hemodiafiltration thrice -weekly during a 24 month follow-up
the comparison of the effects of the two membranes on the serum levels of albumin, B2M, CRP, myoglobin, light chains, retinol binding protein, homocysteine, p-cresol, indoxyl sulfate, BPA, alpha-1-microglobulin (A1M), FGF23 (fibroblast growth factor 23), and inflammatory cytokines; the evaluation of the changes induced by the two filters on lymphocyte subsets, monocyte activation and senescence, and apoptosis rate; the definition of the impact of the two membranes on the accumulation of AGEs as an index of metabolic and oxidative stress, determined by a non-invasive method based on the measurement of skin autofluorescence through a dedicated device (AGE Reader, DiagnOptics Technologies BV, Groningen, Netherlands).

Locations

Country	Name	City	State
Italy	Nephrology Dialysis and Renal Transplantatio Unit, StOrsola University Hospital	Bologna

Sponsors (2)

Lead Sponsor	Collaborator
IRCCS Azienda Ospedaliero-Universitaria di Bologna	University of Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (22)

Desjardins L, Liabeuf S, Lenglet A, Lemke HD, Vanholder R, Choukroun G, Massy ZA; European Uremic Toxin (EUTox) Work Group. Association between free light chain levels, and disease progression and mortality in chronic kidney disease. Toxins (Basel). 2013 Nov 8;5(11):2058-73. doi: 10.3390/toxins5112058. — View Citation

Furuta M, Kuragano T, Kida A, Kitamura R, Nanami M, Otaki Y, Nonoguchi H, Matsumoto A, Nakanishi T. A crossover study of the acrylonitrile-co-methallyl sulfonate and polysulfone membranes for elderly hemodialysis patients: the effect on hemodynamic, nutritional, and inflammatory conditions. ASAIO J. 2011 Jul-Aug;57(4):293-9. doi: 10.1097/MAT.0b013e31821796f1. — View Citation

Georgatzakou HT, Tzounakas VL, Kriebardis AG, Velentzas AD, Kokkalis AC, Antonelou MH, Papassideri IS. Short-term effects of hemodiafiltration versus conventional hemodialysis on erythrocyte performance. Can J Physiol Pharmacol. 2018 Mar;96(3):249-257. doi: 10.1139/cjpp-2017-0285. Epub 2017 Aug 30. — View Citation

Gryp T, Vanholder R, Vaneechoutte M, Glorieux G. p-Cresyl Sulfate. Toxins (Basel). 2017 Jan 29;9(2). pii: E52. doi: 10.3390/toxins9020052. Review. — View Citation

Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008 Aug 7;359(6):584-92. doi: 10.1056/NEJMoa0706130. — View Citation

Hangai M, Takebe N, Honma H, Sasaki A, Chida A, Nakano R, Togashi H, Nakagawa R, Oda T, Matsui M, Yashiro S, Nagasawa K, Kajiwara T, Takahashi K, Takahashi Y, Satoh J, Ishigaki Y. Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence. J Atheroscler Thromb. 2016 Oct 1;23(10):1178-1187. Epub 2016 Mar 10. — View Citation

Himmelfarb J, McMenamin E, McMonagle E. Plasma aminothiol oxidation in chronic hemodialysis patients. Kidney Int. 2002 Feb;61(2):705-16. — View Citation

Hofmann B, Jacobs K, Navarrete Santos A, Wienke A, Silber RE, Simm A. Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease. Diabetes Metab. 2015 Nov;41(5):410-5. doi: 10.1016/j.diabet.2014.12.001. Epub 2014 Dec 29. — View Citation

Hung SC, Kuo KL, Wu CC, Tarng DC. Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease. J Am Heart Assoc. 2017 Feb 7;6(2). pii: e005022. doi: 10.1161/JAHA.116.005022. Review. — View Citation

Kendrick J, Chonchol MB. Nontraditional risk factors for cardiovascular disease in patients with chronic kidney disease. Nat Clin Pract Nephrol. 2008 Dec;4(12):672-81. doi: 10.1038/ncpneph0954. Epub 2008 Sep 30. Review. — View Citation

Kimura H, Tanaka K, Kanno M, Watanabe K, Hayashi Y, Asahi K, Suzuki H, Sato K, Sakaue M, Terawaki H, Nakayama M, Miyata T, Watanabe T. Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis. Ther Apher Dial. 2014 Oct;18(5):461-7. doi: 10.1111/1744-9987.12160. Epub 2014 Jan 24. — View Citation

Liabeuf S, Lenglet A, Desjardins L, Neirynck N, Glorieux G, Lemke HD, Vanholder R, Diouf M, Choukroun G, Massy ZA; European Uremic Toxin Work Group (EUTox). Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients. Kidney Int. 2012 Dec;82(12):1297-303. doi: 10.1038/ki.2012.301. Epub 2012 Aug 15. — View Citation

Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, Klag MJ. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol. 2002 Jul;13(7):1918-27. — View Citation

McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Skin autofluorescence and the association with renal and cardiovascular risk factors in chronic kidney disease stage 3. Clin J Am Soc Nephrol. 2011 Oct;6(10):2356-63. doi: 10.2215/CJN.02420311. Epub 2011 Sep 1. — View Citation

Memoli B, Postiglione L, Cianciaruso B, Bisesti V, Cimmaruta C, Marzano L, Minutolo R, Cuomo V, Guida B, Andreucci M, Rossi G. Role of different dialysis membranes in the release of interleukin-6-soluble receptor in uremic patients. Kidney Int. 2000 Jul;58(1):417-24. — View Citation

Menegatti E, Rossi D, Chiara M, Alpa M, Sena LM, Roccatello D. Cytokine release pathway in mononuclear cells stimulated in vitro by dialysis membranes. Am J Nephrol. 2002 Sep-Dec;22(5-6):509-14. — View Citation

O'Lone E, Viecelli AK, Craig JC, Tong A, Sautenet B, Roy D, Herrington WG, Herzog CA, Jafar T, Jardine M, Krane V, Levin A, Malyszko J, Rocco MV, Strippoli G, Tonelli M, Wang AYM, Wanner C, Zannad F, Winkelmayer WC, Webster AC, Wheeler DC. Cardiovascular Outcomes Reported in Hemodialysis Trials. J Am Coll Cardiol. 2018 Jun 19;71(24):2802-2810. doi: 10.1016/j.jacc.2018.04.012. Review. — View Citation

Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update. Toxins (Basel). 2018 Jan 8;10(1). pii: E33. doi: 10.3390/toxins10010033. Review. — View Citation

Walker RJ, Sutherland WH, De Jong SA. Effect of changing from a cellulose acetate to a polysulphone dialysis membrane on protein oxidation and inflammation markers. Clin Nephrol. 2004 Mar;61(3):198-206. — View Citation

Wang CC, Wang YC, Wang GJ, Shen MY, Chang YL, Liou SY, Chen HC, Chang CT. Skin Autofluorescence Is Associated with Endothelial Dysfunction in Uremic Subjects on Hemodialysis. PLoS One. 2016 Jan 25;11(1):e0147771. doi: 10.1371/journal.pone.0147771. eCollection 2016. — View Citation

Wautier JL, Schmidt AM. Protein glycation: a firm link to endothelial cell dysfunction. Circ Res. 2004 Aug 6;95(3):233-8. Review. — View Citation

Zoccali C. Cardiovascular risk in uraemic patients-is it fully explained by classical risk factors? Nephrol Dial Transplant. 2000 Apr;15(4):454-7. Review. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of uremic toxins	Beta 2 microglobulin (B2M), C-reactive protein (CRP), albumin, myoglobin, light chains, retinol binding protein, homocysteine, p-cresol, indoxyl sulfate, BPA, alpha-2-macroglobulin (A2M), FGF23 (fibroblast growth factor 23)	24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Secondary	Measurement of endothelial cells metabolism	The patients' sera will be incubated with Human Coronary Artery Endothelial Cells (HCAECs), a human cell line isolated from normal coronary arteries. HCAECs are the ideal candidates for the study of endothelial cell functions and metabolism, proving an excellent model system to study all aspects of cardiovascular function and disease	24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Secondary	Patients survival	the mortality rate of the patients will be recorded	24 months
Secondary	Body impedance analysis	Body impedance analysis will be carried out monthly through Electro fluid graph machine	24 months.
Secondary	AGEs measurements	AGEs measurements will be carried out monthly through skin autofluorescence	24 months
Secondary	Measurement of inflammatory cytokines	measurement of interleukin 1 beta (IL-1 ß), interleukin 6 (IL-6), interleukin 10 (IL-10),interleukin 12 p 70 (IL-12 (p70)), interleukin 17 (IL -17), tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-?)	24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Secondary	Measurement of inflammatory cell activation	Measurement of lymphocyte subsets, monocyte activation and senescence, and apoptosis rate	24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Secondary	Infection rate	The number of infections that affected the patients and the rate of hospitalization for infections will be recorded	24 months
Secondary	Cardiovascular diseases	The number of cardiovascular disease that affected the patients and the rate of hospitalization for cardiovascular disease will be recorded	24 months