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• W2016178552 abstract "Is cytokine removal by continuous hemofiltration feasible? Patients who are critically ill with acute renal failure and sepsis have extremely high mortality rates. While it seems reasonable that eliminating the inflammatory mediators (such as cytokines, chemokines, tumor necrosis factor-α, etc.) by continuous renal replacement therapy (CRRT) would be effective, studies show that only insubstantial numbers of these mediators are removed in comparison with endogenous clearance. Mass removal seems only to be effective when highly permeable membranes (sieving coefficient of approximately 1.0) are used, there is a filtrate volume greater than 2 liters/hour, and when the half-life of the substance to be eliminated is greater than 60 minutes. Removal of cytokines by membrane adsorption is another possibility. However, because the membrane surfaces are saturated after a few hours, frequent filter changes are necessary for them to generate effective adsorption of these mediators. Despite filter changes, only a brief and transient drop in the TNF plasma level has been observed. Controlled clinical trials are needed to determine whether or not CRRT actually has a beneficial effect on the systemic inflammatory response syndrome (SIRS). Is cytokine removal by continuous hemofiltration feasible? Patients who are critically ill with acute renal failure and sepsis have extremely high mortality rates. While it seems reasonable that eliminating the inflammatory mediators (such as cytokines, chemokines, tumor necrosis factor-α, etc.) by continuous renal replacement therapy (CRRT) would be effective, studies show that only insubstantial numbers of these mediators are removed in comparison with endogenous clearance. Mass removal seems only to be effective when highly permeable membranes (sieving coefficient of approximately 1.0) are used, there is a filtrate volume greater than 2 liters/hour, and when the half-life of the substance to be eliminated is greater than 60 minutes. Removal of cytokines by membrane adsorption is another possibility. However, because the membrane surfaces are saturated after a few hours, frequent filter changes are necessary for them to generate effective adsorption of these mediators. Despite filter changes, only a brief and transient drop in the TNF plasma level has been observed. Controlled clinical trials are needed to determine whether or not CRRT actually has a beneficial effect on the systemic inflammatory response syndrome (SIRS). A great number of supporting and hampering factors are involved in the complex network that leads to sepsis. These include cytokines, chemokines, adhesion molecules, E-selectin, prostaglandins, and various phagocytic cells of the immune system, the systemic inflammatory response syndrome (SIRS) and the counter-regulatory anti-inflammatory response syndrome (CARS). The inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) cause the same spectrum of clinical symptoms as do staphylococcal exotoxin or gram-negative endotoxins. IL-6, IL-8, and platelet-activating factor are further important elements that stimulate inflammation. Extensive experimental and clinical investigations are now being focused on the concept of blocking the biological properties of IL-1 and TNF. Blocking IL-1 or TNF-α has been highly successful in patients with rheumatoid arthritis, inflammatory bowel disease, or graft-versus-host reaction. However, despite positive experience with animal models, anticytokine therapy for sepsis has been disappointing. Over 13,000 patients with septic shock have entered trials with TNF-α–neutralizing antibodies, soluble TNF-α receptors, and IL-1 receptor antagonists in double-blind, placebo controlled trials1Calandra T. Immunomodulation for Sepsis and Septic Shock.1998Google Scholar, 2Fisher Jr, C.J. Dhainaut J.F. Opal S.M. Pribble J.P. Balk R.A. Slotman G.J. Iberti T.J. Rackow E.C. Shapiro M.J. Greenman R.L. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.JAMA. 1994; 271: 1836-1843Crossref PubMed Scopus (919) Google Scholar, 3McCloskey R.V. Straube R.C. Sanders C. Smith S.M. Smith C.R. Treatment of septic shock with human monoclonal antibody HA-1A.A randomized, double-blind, placebo-controlled trial: CHESS Trial Study Group.Ann Intern Med. 1994; 121: 1-5Crossref PubMed Scopus (386) Google Scholar, 4Abraham E. Wunderink R. Silverman H. Perl T.M. Nasraway S. Levy H. Bone R. Wenzel R.P. Balk R. Allred R. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome: A randomized, controlled, double-blind, multicenter clinical trial. RNF-Alpha Mab Sepsis Study Group.JAMA. 1995; 273: 934-941Crossref PubMed Scopus (749) Google Scholar, 5Cohen J. Carlet J. Intersept: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group.Crit Care Med. 1996; 24: 1431-1440Crossref PubMed Scopus (415) Google Scholar, 6Knaus W.A. Harrell Jr, F.E. LaBrecque J.F. Wagner D.P. Pribble J.P. Draper E.A. Fisher Jr, C.J. Soll L. Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis. The rhIL-1ra Phase III Sepsis Syndrome Study Group.Crit Care Med. 1996; 1: 46-56Crossref Scopus (78) Google Scholar, 7Opal S.M. Fischer Jr, C.J. Dhainaut J.F. Vincent J.L. Brase R. Lowry S.F. Sadoff J.C. Slotman G.J. Levy H. Balk R.A. Shelly M.P. Pribble J.P. LaBrecque J.F. Lookabaugh J. Donovan H. Dubin H. Baughman R. Norman J. Demaria E. Matzel K. Abraham E. Seneff M. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.Crit Care Med. 1997; 7: 1115-1124Crossref Scopus (639) Google Scholar, 8Abraham E. Anzueto A. Gutierrez G. Tessler S. San Pedro G. Wunderink R. Dal Nogare A. Nasraway S. Berman S. Gooney R. Levy H. Baughman R. Rumbak M. Light R.B. Poole L. Allred R. Constant J. Pennington J. Porter S. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group.Lancet. 1998; 351: 929-933Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar. Although a small (2 to 3%) increase in the 28-day survival rate has been reported with anticytokine therapy, the effect is not statistically significant. In fact, increased mortality has been reported by Fisher et al with the TNF receptor Fc fusion protein9Fisher C.H.J. Agosti J.M. Opal S.M. Lowry S.F. Balk R.A. Sadoff J.G. Abraham E. Schein R.M.H. Benjamin E. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein.N Engl J Med. 1996; 334: 1697-1702Crossref PubMed Scopus (1010) Google Scholar. Another method for treating these disease entities has been to eliminate cytokines and chemokines instead of blocking them. A considerable number of experimental and clinical investigators have reported employing hemofiltration, hemodiafiltration, plasmapheresis, and adsorption to eliminate cytokines and chemokines in an attempt to reduce the high mortality of SIRS10Schetz M. Non-renal indications for CRRT.Kidney Int. 1999; 56 (this issue)Google Scholar. One may assume that eliminating cytokines from the plasma can only influence its endocrine, but not the autocrine or paracrine mode of action. Until now, there have been many hints, but no proof, that extracorporeal elimination of septic mediators influences the course of the disease. No studies have been able to prove that the elimination of cytokines improves the survival rate. Most of these studies have been carried out on patients with acute renal failure. In a meta-analytic study comparing intermittently hemodialyzed to continuously hemofiltrated patients, the last group exhibited an approximately 10% better survival rate. However, proof that this improvement was a result of mediator elimination does not exist (abstract; Simpson et al, Nephrol Dial Transplant 8:946, 1993)11Kierdorf H. Sieberth H.G. Continuous treatment modalities in acute renal failure.Nephrol Dial Transplant. 1995; 10: 2001-2008PubMed Google Scholar, 12Mauritz W. Sporn P. Schindler I. Zadrobilek E. Roth E. Appel W. Acute renal failure in abdominal infection: Comparison of hemodialysis and continuous arteriovenous hemofiltration.Anasth Intensivther Notfallmed. 1986; 21: 212-217Crossref PubMed Scopus (40) Google Scholar, 13Alarabi A.A. Danielson B.G. Wikstrom B. Wahlberg J. Outcome of continuous arteriovenous hemofiltration (CAVH) in one centre.Ups J Med Sci. 1989; 94: 299-303Crossref PubMed Scopus (10) Google Scholar, 14Brian R. McDonald B.R. Metha R.L. Decreased mortality in patients with acute renal failure undergoing continuous arteriovenous hemodialysis.Contrib Nephrol. 1991; 93: 51-56Crossref PubMed Google Scholar, 15Bellomo R. Mansfield D. Rumble S. Shapiro J. Parkin G. Boyce N. Acute renal failure in critical illness: Conventional dialysis versus acute continuous hemodiafiltration.ASAIO J. 1992; 38: 654-657Crossref PubMed Scopus (48) Google Scholar, 16Bellomo R. Boyce N. Continuous venovenous hemodiafiltration compared with conventional dialysis in critically ill patients with acute renal failure.ASAIO J. 1993; 30: 794-797Crossref Scopus (46) Google Scholar, 17Kruczynski K. Irvine-Bird K. Toffelmire E.B. Morton A.R. A comparison of continuous arteriovenous hemofiltration and intermittent hemodialysis in acute renal failure patients in the intensive care unit.ASAIO J. 1993; 39: 778-781Crossref PubMed Google Scholar. Other studies have shown that partial respiratory, circulatory, and metabolic failure can be beneficially influenced by continuous hemofiltration. Again, the possibility that this benefit is attributable to the elimination of cytokines has been discussed, but not proven18Coraim F. Fasol R. Stellwag F. Wolner T.L. Continuous arteriovenous hemofiltration (CAVH) after cardiac surgery: Continuous Arteriovenous Hemofiltration (CAVH).International Conference on CAVH. Karger, Aachen, Basel1985: 116-124Crossref Google Scholar, 19Gotloib L. Barzilay E. Shustak A. Wais Z. Jaichenko J. Lev A. Hemofiltration in septic ARDS: The artificial kidney as an artificial endocrine lung.Resuscitation. 1986; 13: 123-132Abstract Full Text PDF PubMed Scopus (70) Google Scholar, 20Bellomo R. Tipping P. Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients.Crit Care Med. 1993; 4: 522-526Crossref Scopus (316) Google Scholar, 21Heering P. Morgera S. Schmitz F.J. Schmitz G. Willers R. Schultheis H.P. Stauer B.E. Grabensee B. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous hemofiltration.Intensive Care Med. 1997; 23: 288-296Crossref PubMed Scopus (223) Google Scholar. The few controlled studies on patients without renal insufficiency, in which the influence of hemofiltration has been investigated, have not clearly shown that mediator elimination positively effects the course of the disease22Sander A. Armbruster W. Sander B. Thurauf N. Lange R. Peters J. Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNFα plasma concentrations.Intensive Care Med. 1997; 23: 878-884Crossref PubMed Scopus (118) Google Scholar, 23Braun N. Rosenfeld S. Giolai M. Banzhaf W. Fretscher R. Warth H. Weinstock C. Deppisch R. Erley C.M. Muller G.A. Risler T. Effect of continuous hemodiafiltration on IL-6, TNF-α, C3a, and TCC in patients with SIRS/septic shock using two different membranes.Contrib Nephrol. 1995; 116: 89-98Crossref PubMed Google Scholar, 24Riegel W. Ziegenfuss T. Rose S. Bauer M. Marzi I. Influence of venovenous hemofiltration on posttraumatic inflammation and hemodynamics.Contrib Nephrol. 1995; 116: 56-61Crossref PubMed Google Scholar, 25Cosentino F. Paganini E. Lockrem J. Stoler J. Wiedemann H. Continuous arteriovenous hemofiltration in the adult respiratory distress syndrome.Contrib Nephrol. 1991; 93: 94-97Crossref PubMed Google Scholar. Even studies in hemofiltrated patients with improving circulatory conditions or in patients receiving less catecholamine support could not show that mediator elimination positively influenced the course of the disease26Bellomo R. Baldwin I. Cole L. Ronco C. Preliminary experience with high-volume hemofiltration in human septic shock.Kidney Int. 1998; 53: 182-185Google Scholar,27Wakabayashi Y. Kamijou Y. Soma K. Ohwada T. Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome of multiple organ dysfunction syndrome.Br J Surg. 1996; 83: 393-394Crossref PubMed Scopus (29) Google Scholar. In animal models, the survival length and rate after exposure to exotoxins and endotoxins can be improved by the early initiation of hemofiltration28Staubach K.H. Rau H.G. Kooistra A. Shardey H.M. Hohlbach G. Schildberg F.W. Can hemofiltration increase survival in acute endotoxemia: A porcine shock model.Prog Clin Biol Res. 1989; 308: 821-826PubMed Google Scholar, 29Stein B. Pfenninger E. Grunert A. Schmitz J.E. Hudde M. Influence of continuous haemofiltration on haemodynamics and central blood, in experimental endotoxic shock.Intensive Care Med. 1990; 16: 494-499Crossref PubMed Scopus (108) Google Scholar, 30Heidemann S.M. Ofenstein J.P. Sarnaik A.P. Efficacy of continuous arteriovenous hemofiltration in endotoxic shock.Circ Shock. 1994; 44: 183-187PubMed Google Scholar, 31Lee P.A. Weger G.W. Pryror R.W. Matson J.R. Effects of filter pore size on efficacy of continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine.Crit Care Med. 1998; 26: 730-737Crossref PubMed Scopus (70) Google Scholar, and infusion of the filtrate can induce septic symptoms in healthy animals. However, it has not been proven that these symptoms are caused by mediators, as it is possible that filtered exotoxins may induce the septic symptoms32Lee P.A. Matson J.R. Pryor R.W. Hinshaw L.B. Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine?.Crit Care Med. 1993; 21: 914-924Crossref PubMed Scopus (92) Google Scholar. Hemofiltration has shown no beneficial effect in animal models in which an infection such as peritonitis, instead of exotoxins or indotoxins, was employed to induce sepsis33Freeman B.D. Yatsiv I. Natanson C. Solomon M.A. Quezado Z.M.N. Danner R.L. Banks S.M. Hoffman W. Continuous arteriovenous hemofiltration does not improve survival in a canine model of septic shock.J Am Coll Surg. 1995; 180: 286-292PubMed Google Scholar. A series of investigations has shown that hemofiltration does remove cytokines from the circulation by convection20Bellomo R. Tipping P. Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients.Crit Care Med. 1993; 4: 522-526Crossref Scopus (316) Google Scholar, 21Heering P. Morgera S. Schmitz F.J. Schmitz G. Willers R. Schultheis H.P. Stauer B.E. Grabensee B. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous hemofiltration.Intensive Care Med. 1997; 23: 288-296Crossref PubMed Scopus (223) Google Scholar, 34Bellomo R. Tipping P. Boyce N. Tumor necrosis factor clearances during veno-venous hemofiltration in the critically ill.Trans Am Soc Artif Intern Organs. 1991; 37: 322-332Google Scholar, 35Barrera P. Janssen E.M. Demacker P.N.M. Wetzels J.F.M. Van der Meer J.W.M. Removal of interleukin-1beta and tumor necrosis factor from human plasma by in vitro dialysis with polyacrylonitrile membranes.Lymphokine Cytokine Res. 1992; 11: 99-104PubMed Google Scholar, 36Lonnemann G. Schindler R. Dinarello C.A. Koch K.M. Removal of circulating cytokines by hemodialysis membranes in vitro,.in: Faist E. Meakins J. Schildberg F.W. Host Defense Dysfunction in Shock and Sepsis. Springer Verlag, Berlin-Heidelberg1992: 613-623Google Scholar, 37Goldfarb S. Golper T.A. Proinflammatory cytokines and hemofiltration membranes.J Am Soc Nephrol. 1994; 5: 228-232PubMed Google Scholar, 38Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 39Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (47) Google Scholar. Commonly, removal is expressed as a percentage of the blood or plasma concentration, and not as a portion of the total body amount or with respect to the metabolic clearance rate. Effective blood purification, and also in the case of mediators, generally takes place under three conditions: (a) The extracorporeally eliminated amount must be of consequence when regarding the total body amount. (b) With respect to the endogenous clearance rate, the extracorporeal clearance rate must be so high that (c) the amount eliminated extracorporeally beneficially influences the course of the disease. It is not clear whether or not the elimination of isolated sepsis or SIRS-related factors can influence the course of the disease. It is also possible that removal of isolated mediators after a prolonged course of the disease is no longer beneficial. According to Fong et al, “Hence, the entire milieu of hormonal and cytokine mediators must be considered in the assessment of postinjury biologic response”40Fong J. Moldawer L.L. Shires G.T. Lowry S.F. The biological characteristics of cytokines and their implication in surgical injury.Surg Gynecol Obstet. 1990; 170: 365-378Google Scholar. To judge the quality of an elimination process, it is necessary to determine not only a concentration difference but the total amount eliminated (mass removal). The appropriate measurements are shown in Table 1. Because cytokines occur in different fluids, internal standards should be contained in those fluids under investigation. It should be kept in mind that values attained with an enzyme-linked immunosorbent assay (ELISA) may not be the same as those achieved with a bioassay. This is particularly true for TNF-α, which is inactive in the monomeric form but active in the trimeric form.Table 1Extracorporeal mass removal (mass removal during endogenous half-life) Open table in a new tab Before judging the efficiency of a procedure, the amount of a substance eliminated extracorporeally must be established in relationship to the endogenous clearance Table 2.Table 2Efficacy of blood purification Open table in a new tab Aside from the parameters listed in Table 1, the following parameters are necessary for a calculation: molecular weight41Callard R. Gearing A. The Cytokine Facts Book. Academic Press Harcourt Brace & Company, London, San Diego1994Google Scholar, sieving coefficient in vivo10Schetz M. Non-renal indications for CRRT.Kidney Int. 1999; 56 (this issue)Google Scholar, 20Bellomo R. Tipping P. Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients.Crit Care Med. 1993; 4: 522-526Crossref Scopus (316) Google Scholar, 21Heering P. Morgera S. Schmitz F.J. Schmitz G. Willers R. Schultheis H.P. Stauer B.E. Grabensee B. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous hemofiltration.Intensive Care Med. 1997; 23: 288-296Crossref PubMed Scopus (223) Google Scholar, 37Goldfarb S. Golper T.A. Proinflammatory cytokines and hemofiltration membranes.J Am Soc Nephrol. 1994; 5: 228-232PubMed Google Scholar, 38Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 39Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (47) Google Scholar, 42Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Cytokine kinetics (TNF-alpha, IL-1beta, IL-6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar, virtual distribution volume in the body43Blick M. Sherwin S.A. Rosenblum M. Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients.Cancer Res. 1987; 47: 2986-2989PubMed Google Scholar, and internal elimination rate (half-life)40Fong J. Moldawer L.L. Shires G.T. Lowry S.F. The biological characteristics of cytokines and their implication in surgical injury.Surg Gynecol Obstet. 1990; 170: 365-378Google Scholar, 43Blick M. Sherwin S.A. Rosenblum M. Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients.Cancer Res. 1987; 47: 2986-2989PubMed Google Scholar, 44Lotze M.T. Robb R.J. Sharrow S.A. Systemic administration of interleukin-2 in humans.J Biol Response Mod. 1984; 3: 475-482PubMed Google Scholar, 45Beutler B.A. Milsark I.W. Cerami A. Cachectin/tumor necrosis factor: Production, distribution, and metabolic fate in vivo.J Immunol. 1985; 135: 3972-3977PubMed Google Scholar, 46Newton R.C. Uhl J. Covington M. Back O. The distribution and clearance of radiolabeled human interleukin-1 beta in mice.Lymphokine Res. 1988; 7: 207-216PubMed Google Scholar, 47Lowry S.F. Van Zee K.J. Rock C.S. Thompson W.A. Oldenburg H.S.A. Rogy M.A. Moldawer L.L. Tumor necrosis factor as a mediator of sepsis.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 13-14Crossref Google Scholar, 48Moldawer L.L. Fischer E. Van Lee K.J. Thompson W.A. Lowry S.F. A role for interleukin-1 in septic shock.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 18-25Crossref Google Scholar, 49Castell J. Klapproth J. Gross V. Eike W.E. Andus T. Snyers L. Content J. Heinrich P.C. Fate of interleukin-6 in the rat.Eur J Biochem. 1990; 189: 113-118Crossref PubMed Scopus (42) Google Scholar, 50Borth W. Luger T.A. Identification of α2-macroglobulin as a cytokine binding plasma protein.J Biol Chem. 1989; 264: 5818-5825Abstract Full Text PDF PubMed Google Scholar. These reference data are listed in Table 3. Considering their molecular weights, a higher sieving coefficient could be expected for most of the cytokines. However, binding to circulating receptors or other proteins and secondary membrane formation in the hemofilters result in a decrease in the sieving coefficient. That may be one reason why the coefficients vary considerably between investigators, between different membrane types, and are not constant during the course of filtration. However, because of the short metabolic half-life, this variability is of little significance when purifying the blood of cytokines.Table 3Molecular weight, sieving coefficients and endogenous half-lives of some cytokinesCytokinesMolecular weightSieving coefficientHalf-life minutesTNFα∼17.40–0.2,aData are from the literature10 0.01–1.052De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar∼6–745Beutler B.A. Milsark I.W. Cerami A. Cachectin/tumor necrosis factor: Production, distribution, and metabolic fate in vivo.J Immunol. 1985; 135: 3972-3977PubMed Google Scholar ∼14–1743Blick M. Sherwin S.A. Rosenblum M. Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients.Cancer Res. 1987; 47: 2986-2989PubMed Google Scholar monomer∼1547Lowry S.F. Van Zee K.J. Rock C.S. Thompson W.A. Oldenburg H.S.A. Rogy M.A. Moldawer L.L. Tumor necrosis factor as a mediator of sepsis.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 13-14Crossref Google Scholar trimer∼52IL-1∼180.07–0.42,bRising sieving coefficient during hemofiltration 0.3538Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (120) Google Scholar 0.1839Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (47) Google Scholar, 0.12–1.052De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar∼6–1044Lotze M.T. Robb R.J. Sharrow S.A. Systemic administration of interleukin-2 in humans.J Biol Response Mod. 1984; 3: 475-482PubMed Google ScholarIL-2∼6–1046Newton R.C. Uhl J. Covington M. Back O. The distribution and clearance of radiolabeled human interleukin-1 beta in mice.Lymphokine Res. 1988; 7: 207-216PubMed Google ScholarIL-6∼260.01–0.3252De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar∼649Castell J. Klapproth J. Gross V. Eike W.E. Andus T. Snyers L. Content J. Heinrich P.C. Fate of interleukin-6 in the rat.Eur J Biochem. 1990; 189: 113-118Crossref PubMed Scopus (42) Google ScholarIL-8∼6–80.0–0.48,bRising sieving coefficient during hemofiltration 0.4439Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (47) Google Scholara Data are from the literature10Schetz M. Non-renal indications for CRRT.Kidney Int. 1999; 56 (this issue)Google Scholarb Rising sieving coefficient during hemofiltration Open table in a new tab The distribution volume of cytokines with a molecular weight below 20 kDa should correspond to at least the extracorporeal space, which entails approximately 15% of the body weight. Determination of the half-life of the cytokines raises some problems. It is possible to estimate the half-life after one dose of a labeled cytokine49Castell J. Klapproth J. Gross V. Eike W.E. Andus T. Snyers L. Content J. Heinrich P.C. Fate of interleukin-6 in the rat.Eur J Biochem. 1990; 189: 113-118Crossref PubMed Scopus (42) Google Scholar or by the slope of the curve after a single application of an exotoxin or endotoxin. However, continuous formation of cytokines must be considered47Lowry S.F. Van Zee K.J. Rock C.S. Thompson W.A. Oldenburg H.S.A. Rogy M.A. Moldawer L.L. Tumor necrosis factor as a mediator of sepsis.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 13-14Crossref Google Scholar. No reference data are available for the half-life of cytokines in patients with SIRS, where increased formation occurs. For the subsequent calculations, a half-life for TNF-α of 15 minutes has been employed, which corresponds to the half-life of other cytokines. An extracellular space of 15 liters and a filtration volume of 1 liter/hr and a relatively high sieving coefficient for TNF-α of 0.25 are assumed. With a plasma TNF-α concentration of 500 pg/ml or 500 ng/liter and an extracellular volume of 15 liters, a total amount of approximately 7500 ng TNF-α is calculated. During the 15-minute half-life, roughly 3750 ng are metabolized while at the same time, 250 ml filtrate with approximately 30 ng TNF-α is removed. Comparing the metabolized amount of TNF-α and the amount removed by hemofiltration, a mass transfer by hemofiltration of only approximately 1% occurs. Increasing the sieving coefficient to 1 increases the amount removed by hemofiltration to approximately 4%. In Table 4, the mass removal of a single mediator with different filtrate volumes and sieving coefficients is calculated. The calculation with higher sieving coefficients demonstrates the mass transfer that can occur with membrane improvement. Because no data are available about the half-life of mediators in patients with sepsis or SIRS, the calculations are carried out with half-lives of up to 120 minutes.Table 4Mass removal by hemofiltration (%) in relation to the endogenous half-life and dependence of filtrate volume and the sieving coefficientFiltrate volumeSieving coefficientHalf-life of mediator, 100% endogenously removed15 min30 min60 min120 min1 liter/hr0.10.30.61.22.41 liter/hr0.2512481 liter/hr0.5248161 liter/hr14816322 liter/hr0.10.61.22.44.82 liter/hr0.25248162 liter/hr0.54816322 liter/hr1.08163264 Open table in a new tab The question of whether continual renal replacement therapy (CRRT) has a beneficial effect on sepsis or SIRS can be clarified only in controlled studies. Whether or not substantial amounts of various mediators can be removed by hemofiltration must be established by measurement. The results presented here with relevant data show that hemofiltration can only remove insubstantial amounts of mediators, representing only a few percentages, compared with endogenous clearance. In concurrence, most investigators have reported no (abstract; Kierdorf et al, Ren Fail 14:98, 1992)27Wakabayashi Y. Kamijou Y. Soma K. Ohwada T. Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome of multiple organ dysfunction syndrome.Br J Surg. 1996; 83: 393-394Crossref PubMed Scopus (29) Google Scholar,42Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Cytokine kinetics (TNF-alpha, IL-1beta, IL-6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar or only minimal decreases in the plasma mediator concentration51Kellum J.A. Johnson J.P. Kramer S. Palevsky P. Brady J.J. Pinsky M.R. Diffusive versus convective therapy: Effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome.Crit Care Med. 1998; 26: 1995-2000Crossref PubMed Scopus (188) Google Scholar, even when employing hemofiltration over several days. An effective mass removal is only possible with a highly permeable membrane (sieving coefficient approximately 1.0), a high filtrate volume (≥2 liter/hr), and when the half-life of the substance to be eliminated is greater than 60 minutes. Membrane adsorption has not been taken into account in these calculations. Adsorption onto the majority of membranes generally in use is low and only for polyacrylonitrile membranes relatively high52De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar. However, within a few hours, the adsorption on the membrane surface is saturated. Frequent filter change or developing special filters might generate more efficient adsorption, perhaps with better mass removal of mediators encountered during sepsis, but even during treatment with this type of membrane, only a short transient drop of the TNF plasma level could be observed. Following disappointing results of treating sepsis or SIRS with antibodies and receptor blockers for cytokines, hope had been invested in removing these substances by blood purification. The calculations presented here show that continuous hemofiltration can remove only insubstantial amounts of mediators when compared with endogenous clearance. This does not mean that continuous renal replacement therapy (CRRT) cannot positively influence sepsis or SIRS in other ways." @default.
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