REmoval of Free Light Chains. A COmpaRison of Three Different dialyzERs

Complication of Hemodialysis Clinical Trial

— RECORDER  

Official title:

REmoval of Free Light Chains in Hemodialysis Patients Without Multiple Myeloma. A Crossover COmpaRison of Three Different dialyzERs

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02950389
• Other study ID #: 2016/GD/2
• Status: Completed
• Phase: N/A
• Start date: January 2016
• Est. completion date: July 2016

Study information

• Verified date: March 2021
• Source: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Immunoglobulin light chains are classified as middle molecule uremic toxins able to interact with B lymphocyte membranes leading to the activation of transmembrane signaling. The ensuing impairment of neutrophil function can contribute to the chronic inflammation state of uremic patients, and the increased risk of bacterial infections or vascular calcifications. The aim of this crossover observational study was to assess the difference in free light chain removal by three different hemodialysis filters in patients not affected by multiple myeloma. Free light chain removal was compared in the polymethylmethacrylate (PMMA) membrane Filtryzer BK-F, the polyphenylene HFR17 filter and the conventional polysulfone filter F7 High Performance dialysers (HPS). Twenty chronic hemodialysis patients were enrolled. The patients were randomized into two groups of treatment lasting six weeks each. The dialysis sessions checked were the midweek sessions and the blood was drawn at times 0, 120' and 240'. Kappa (k) and lambda (l) light chain levels, beta2microglobulin (β2M), C reactive protein (CRP) and albumin were checked.

Description:

Background. Immunoglobulin light chains are classified as middle molecule uremic toxins together with β2M and parathyroid hormon. They have a mean molecular weight of 25,000 daltons for monomers (k free light chains) and approximately 50,000 daltons for dimers (lambda free light chains). Raised serum levels of polyclonal free light chains can impair neutrophil function in terms of: 1) inhibited chemotactic movement; 2) reduced activation of glucose uptake; 3) inhibited apoptosis. Immunoglobulin light chains are able to interact with B lymphocyte membranes leading to the activation of transmembrane signaling . The ensuing impairment of neutrophil function can contribute to the chronic inflammation state of uremic patients and to the increased risk of bacterial infection. Desjardins et al. demonstrated an association between free light chain levels and vascular calcification progression in chronic kidney disease patients. Nonetheless, serum free light chains in patients with chronic kidney disease are associated with the risk of end stage renal disease and death. It seems that high flux PMMA membranes significantly reduce the light chain level, presumably due to adsorption. This behavior has led to the use of PMMA in the removal of monoclonal free light chains during multiple myeloma. Preliminary reports describe a significant reduction in free light chains also during hemodiafiltration with reinfusion of endogenous ultrafiltrate (on-line HFR). A recent paper by Borrelli et al. reported an improvement in chronic inflammation after chronic online HFR in dialysis patients. The aim of this crossover observational study was to compare free light chain removal by three different hemodialysis filters in a cohort of chronic dialysis patients not affected by multiple myeloma. Methods. One hundred and sixty-three patients on chronic hemodialysis at the Nephrology, Dialysis and Transplantation Unit of S.Orsola University Hospital in Bologna were considered for the study. The inclusion criteria were free light chain values >100 mg/L for k chains and >50 mg/L for lambda chains. These levels were chosen arbitrarily because no cut-off levels are available in the literature for the assessment of lowered serum free light chain values during hemodialysis in patients with end-stage renal disease. Other inclusion criteria were: age >18 years, absence or <200 ml/die residual diuresis, fistula or central venous catheter with blood flow >250 ml/min. Exclusion criteria were: intradialytic hypotension during bicarbonate dialysis, multiple myeloma requiring the double PMMA filter application, poly-allergy, HIV positivity. The filters used during the study were: i) HFR17 (Bellco, Mirandola, Italy), a double chamber filter used for online HFR. The first part of the filter consisted in a polyphenylene high flux hemofilter with an ultrafiltration coefficient (Kuf) of 28 ml/h/mmHg, a surface area of 0.7 m2 and a membrane cut-off value of 35,000 daltons. The endogenous ultrafiltrate rate is obtained automatically by means of the transmembrane pressure levels in the hemofilter. These are calculated from two pressure sensors: the first is on the arterial bubble chamber and the second before the roller pump of the ultrafiltrate. The ultrafiltrate is driven from this hemofilter to a 40 g neutral styrenic resin that allows an adsorbing area of 28,000 m2. After adsorption, the ultrafiltrate is added to the whole blood that, in turn, passes into the second HFR17 filter, a polyphenylene low flux filter (Kuf 13 ml/h/mmHg, surface area 1.7 m2) where the weight loss and diffusive depuration take place. ii) PMMA (Toray Filtryzer BK-F, Tokyo, Japan) with a surface area of 2.1 m2, a membrane cut-off value of 20,000 daltons and an ultrafiltration coefficient (Kuf) of 26 ml/h/mmHg. iii) A conventional polysulfone membrane (Fresenius F7HPS, Bad Homburg, Germany) with a cut-off of 11,500 daltons, a Kuf of 16 ml/h/mmHg and a surface area of 1.7 m2 was used as a control dialyzer. The patients enrolled were randomized into two groups of treatments lasting six weeks each. Group A: 1st and 2nd weeks with bicarbonate dialysis and filter PMMA, 3rd and 4th weeks with filter HFR17, 5th and 6th weeks with bicarbonate dialysis filter F7. Group B: 1st and 2nd weeks with filter HFR17, 3rd and 4th weeks with bicarbonate dialysis and filter PMMA, 5th and 6th weeks with bicarbonate dialysis filter F7. The dialysis sessions carried out during weeks 1, 3 and 5 were considered washout sessions between weeks 2, 4 and 6 when the assessment of lambda and k light chains, β2M, C reactive protein and albumin was scheduled. Week number 1 was the washout period between the usual dialytic treatment of the patients enrolled and the beginning of the study. The checking dialysis session was the midweek session and the blood was drawn on starting dialysis (time 0), at two hours (time 120') and at dialysis end (time 240'). All the dialysis sessions lasted four hours. Mean blood flow was 310±30 ml/min, the mean ultrafiltration rate was 700±200 ml/h, during HFR the endogenous ultrafiltrate rate was 2.3±0.4 ml/h. Dialysate flow was 500 ml/min. Low molecular weight heparin enoxaparin (Clexane®, Sanofi, Milan, Italy) was used for anticoagulation of the extracorporeal circuit. Doses of 2000 IU (patients <50 kg of body weight), 4000 IU (patients between 50 to 90 kg of body weight) or 6000 IU (patients >90 kg of body weight) were administered in a single bolus on starting dialysis. Fresenius 5008 and Bellco Flexya dialysis machines were used. The concentrations of k and lambda light chains and β2M were measured by nephelometry (kit Freelite k/lambda, The Binding Site Group Ltd., Birmingham, United Kingdom; IIMAGE/IMMAGE 800 Beckman Coulter instrument, Brea California USA, Beckman Coulter β2M kit). Normal values: k light chains 3.3 -19.9 mg/L, lambda light chains 5.7-26.3 mg/L, β2M 0.7 - 2 mg/L. Molecular weights: k light chains: 22,500 daltons; lambda light chains: 45,000 daltons; β2M: 11,818 daltons. The reference range for patients with normal kidney function was considered between 0.26 and 1.65 according to Bourguignon et al.. CRP concentration was measured by turbidimetry (CRPLX, Tina-quant C-Reactive-Protein; Roche/Hitachi 902 analyzer). CRP normal value < 0.8 mg/dl, molecular weight 120,000 daltons. Albumin was assessed using the common laboratory method. The reduction rate per session (RRs) was calculated as follows: RRs = (Cpre- Cpost-corr)/ Cpre x 100 (1) where Cpre is the predialysis solute level, and Cpost-corr is the post-dialysis solute concentration. The values measured during dialysis were corrected for hemoconcentration due to the patient's weight loss assuming a unicompartmental behavior of light chains described by the following formula: Cpost-corr = Cpost/ {1+ [DeltaBW/(0.2xBWpost)]} (2) where Cpost-corr is the post-dialysis solute concentration and Cpost-corr is the concentration of light chains corrected for the hemoconcentration, Delta body weight (DeltaBW) is the weight subtracted during dialysis, and BW (body weight) is the body weight at the end of dialysis. Statistical analyses. Statistical analysis was performed using the "Statistical package for the social sciences (SPSS)" statistical software. The data are presented as mean ± standard error of the mean. The Shapiro-Wilk test, suitable for small populations, showed a non-normal distribution of the variables, for which the non-parametric Friedman test was used. The p value <0.05 was considered normal. The Wilcoxon Signed Rank Test was subsequently used to see which pairwise comparisons resulted statistically different. In addition, as a multiple comparison was done, we applied the Bonferroni correction, thereby setting a p value = 0.05 / 3 = 0.0167. For each of the sampling times 0.120 and 240 minutes, we compared the results and the RRs obtained with the different filters (HFR17, PMMA, F7).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: July 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• chronic hemodialysis patients
• free light chain values >100 mg/L for k chains or >50 mg/L for lambda chains.
• absence or <200 ml/die residual diuresis
• fistula or central venous catheter with blood flow >250 ml/min.

Exclusion Criteria:

• intradialytic hypotension
• multiple myeloma
• poly-allergy
• HIV positivity

Related Conditions & MeSH terms

• Complication of Hemodialysis

Intervention

Device:
• PMMA filter

• HFR17 filter

• F7 filter

Locations

Country	Name	City	State
Italy	Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital	Bologna

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS Azienda Ospedaliero-Universitaria di Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (22)

Aoike I. Clinical significance of protein adsorbable membranes--long-term clinical effects and analysis using a proteomic technique. Nephrol Dial Transplant. 2007 Jul;22 Suppl 5:v13-9. Review. — View Citation

Bergström J, Wehle B. No change in corrected beta 2-microglobulin concentration after cuprophane haemodialysis. Lancet. 1987 Mar 14;1(8533):628-9. — View Citation

Birk HW, Kistner A, Wizemann V, Schütterle G. Protein adsorption by artificial membrane materials under filtration conditions. Artif Organs. 1995 May;19(5):411-5. — View Citation

Borrelli S, Minutolo R, De Nicola L, De Simone E, De Simone W, Zito B, Guastaferro P, Nigro F, Iulianiello G, Credendino O, Bassi A, Leone L, Capuano M, Auricchio MR, Conte G. Effect of hemodiafiltration with endogenous reinfusion on overt idiopathic chronic inflammation in maintenance hemodialysis patients: a multicenter longitudinal study. Hemodial Int. 2014 Oct;18(4):758-66. doi: 10.1111/hdi.12178. Epub 2014 May 28. — View Citation

Bourguignon C, Chenine L, Bargnoux AS, Leray-Moragues H, Canaud B, Cristol JP, Morena M. Hemodiafiltration improves free light chain removal and normalizes ?/? ratio in hemodialysis patients. J Nephrol. 2016 Apr;29(2):251-257. doi: 10.1007/s40620-015-0207-z. Epub 2015 May 29. — View Citation

Cianciolo G, Colí L, La Manna G, Donati G, D'Addio F, Comai G, Ricci D, Dormi A, Wratten M, Feliciangeli G, Stefoni S. Is beta2-microglobulin-related amyloidosis of hemodialysis patients a multifactorial disease? A new pathogenetic approach. Int J Artif Organs. 2007 Oct;30(10):864-78. — View Citation

Cohen G, Rudnicki M, Schmaldienst S, Hörl WH. Effect of dialysis on serum/plasma levels of free immunoglobulin light chains in end-stage renal disease patients. Nephrol Dial Transplant. 2002 May;17(5):879-83. — View Citation

Cohen G. Immunoglobulin light chains in uremia. Kidney Int Suppl. 2003 May;(84):S15-8. Review. — View Citation

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

Donati G, La Manna G, Cianciolo G, Grandinetti V, Carretta E, Cappuccilli M, Panicali L, Iorio M, Piscaglia F, Bolondi L, Colì L, Stefoni S. Extracorporeal detoxification for hepatic failure using molecular adsorbent recirculating system: depurative efficiency and clinical results in a long-term follow-up. Artif Organs. 2014 Feb;38(2):125-34. doi: 10.1111/aor.12106. Epub 2013 Jul 3. — View Citation

Fabbrini P, Sirtori S, Casiraghi E, Pieruzzi F, Genovesi S, Corti D, Brivio R, Gregorini G, Como G, Carati ML, Viganò MR, Stella A. Polymethylmethacrylate membrane and serum free light chain removal: enhancing adsorption properties. Blood Purif. 2013;35 Suppl 2:52-8. doi: 10.1159/000350849. Epub 2013 May 3. — View Citation

Harding S, Provot F, Beuscart JB, Cook M, Bradwell AR, Stringer S, White D, Cockwell P, Hutchison CA. Aggregated serum free light chains may prevent adequate removal by high cut-off haemodialysis. Nephrol Dial Transplant. 2011 Apr;26(4):1438. doi: 10.1093/ndt/gfr019. Epub 2011 Mar 15. — View Citation

Haynes R, Hutchison CA, Emberson J, Dasgupta T, Wheeler DC, Townend JN, Landray MJ, Cockwell P. Serum free light chains and the risk of ESRD and death in CKD. Clin J Am Soc Nephrol. 2011 Dec;6(12):2829-37. doi: 10.2215/CJN.03350411. Epub 2011 Oct 27. — View Citation

Hutchison CA, Bladé J, Cockwell P, Cook M, Drayson M, Fermand JP, Kastritis E, Kyle R, Leung N, Pasquali S, Winearls C; International Kidney and Monoclonal Gammopathy Research Group. Novel approaches for reducing free light chains in patients with myeloma kidney. Nat Rev Nephrol. 2012 Feb 21;8(4):234-43. doi: 10.1038/nrneph.2012.14. Review. — View Citation

Lamy T, Henri P, Lobbedez T, Comby E, Ryckelynck JP, Ficheux M. Comparison between on-line high-efficiency hemodiafiltration and conventional high-flux hemodialysis for polyclonal free light chain removal. Blood Purif. 2014;37(2):93-8. doi: 10.1159/000357968. Epub 2014 Mar 1. — View Citation

Machiguchi T, Tamura T, Yoshida H. Efficacy of haemodiafiltration treatment with PEPA dialysis membranes in plasma free light chain removal in a patient with primary amyloidosis. Nephrol Dial Transplant. 2002 Sep;17(9):1689-91. — View Citation

Pasquali S, Iannuzzella F, Corradini M, Mattei S, Bovino A, Stefani A, Palladino G, Caiazzo M. A novel option for reducing free light chains in myeloma kidney: supra-hemodiafiltration with endogenous reinfusion (HFR). J Nephrol. 2015 Apr;28(2):251-4. doi: 10.1007/s40620-014-0130-8. Epub 2014 Aug 23. — View Citation

Rousseau-Gagnon M, Agharazii M, De Serres SA, Desmeules S. Effectiveness of Haemodiafiltration with Heat Sterilized High-Flux Polyphenylene HF Dialyzer in Reducing Free Light Chains in Patients with Myeloma Cast Nephropathy. PLoS One. 2015 Oct 14;10(10):e0140463. doi: 10.1371/journal.pone.0140463. eCollection 2015. — View Citation

Santoro A, Grazia M, Mancini E. The double polymethylmethacrylate filter (DELETE system) in the removal of light chains in chronic dialysis patients with multiple myeloma. Blood Purif. 2013;35 Suppl 2:5-13. doi: 10.1159/000350837. Epub 2013 May 3. Review. — View Citation

Stefoni S, Colì L, Cianciolo G, Donati G, Ruggeri G, Ramazzotti E, Pohlmeier R, Lang D. Inflammatory response of a new synthetic dialyzer membrane. A randomised cross-over comparison between polysulfone and helixone. Int J Artif Organs. 2003 Jan;26(1):26-32. — View Citation

Testa A, Dejoie T, Lecarrer D, Wratten M, Sereni L, Renaux JL. Reduction of free immunoglobulin light chains using adsorption properties of hemodiafiltration with endogenous reinfusion. Blood Purif. 2010;30(1):34-6. doi: 10.1159/000316684. Epub 2010 Jun 24. — View Citation

Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W; European Uremic Toxin Work Group (EUTox). Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003 May;63(5):1934-43. Review. Erratum in: Kidney Int. 2020 Nov;98(5):1354. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare free light chain removal by three different hemodialysis filters in a cohort of chronic dialysis patients not affected by multiple myeloma		45 days
Secondary	Compare beta 2 microglobulin removal by three different hemodialysis filters		45 days