The KTx360°-study: a multicenter, multisectoral, multimodal, telemedicine-based follow-up care model to improve care and reduce health-care costs after kidney transplantation in children and adults.

BACKGROUND: Follow-up care after kidney transplantation is performed in transplant centers as well as in local nephrologist's practices in Germany. However, organized integrated care of these different sectors of the German health care system is missing. This organizational deficit as well as non-adherence of kidney recipients and longterm cardiovascular complications are major reasons for an impaired patient and graft survival. METHODS: The KTx360° study is supported by a grant from the Federal Joint Committee of the Federal Republic of Germany. The study will include 448 (39 children) incident patients of all ages with KTx after study start in May 2017 and 963 (83 children) prevalent patients with KTx between 2010 and 2016. The collaboration between transplant centers and nephrologists in private local practices will be supported by internet-based case-files and scheduled virtual visits (patient consultation via video conferencing). At specified points of the care process patients will receive cardiovascular and adherence assessments and respective interventions. Care will be coordinated by an additional case management. The goals of the study will be evaluated by an independent institute using claims data from the statutory health insurances and data collected from patients and their caregivers during study participation. To model longitudinal changes after transplantation and differences in changes and levels of immunosuppresive therapy after transplantation between study participants and historical data as well as data from control patients who do not participate in KTx360°, adjusted regression analyses, such as mixed models with repeated measures, will be used. Relevant confounders will be controlled in all analyses. DISCUSSION: The study aims to prolong patient and graft survival, to reduce avoidable hospitalizations, co-morbidities and health care costs, and to enhance quality of life of patients after kidney transplantation. TRIAL REGISTRATION: ISRCTN29416382 (retrospectively registered on 05.05.2017).

Biosimilar epoetin zeta in nephrology - a single-dialysis center experience.

AIM: An observational clinical study was performed to test the efficiency of the biosimilar product epoetin zeta to maintain stable hemoglobin levels in end-stage renal disease (ESRD) patients on intermittent high-flux hemodialysis. PATIENTS AND METHODS: Before the start of the study, 17 out of 18 patients were on various erythropoiesis-stimulating agents (ESA). After a run-in period of 2 months, all patients switched to epoetin zeta and were followed for 6 months. The initial weekly doses as well as the frequency of application per week were kept constant. To convert patients on darbepoetin (n = 12) to epoetin zeta, a factor of 1 : 200 was used. During the follow-up, hemoglobin levels, iron status, dialysis efficiency, body weight, and adverse events were monitored at least once a month. RESULTS: Comparing time 0 (before the start of epoetin zeta) with the end of the study (6 months of epoetin zeta), no significant changes were observed: Hemoglobin 11.72 ± 0.64 g/dl versus 11.62 ± 0.70 g/dl (p = 0.64); weekly dose of ESA: 79.4 ± 57.7 IU/kg/week at start versus 91.8 ± 65.4 IU/kg/week at the end (p = 0.55). It is noteworthy that the frequency of application could be reduced to once a week or less with epoetin zeta in 66% of the 18 patients. After 6 months of epoetin zeta, 10 patients received 1 dose/week, and 2 patients received only 1 dose every 2 weeks. There were no significant changes in mean blood pressure, body weight and hemodialysis efficiency comparing the end with the start of the observation. No side effects attributable to the ESA-therapy have been observed. CONCLUSION: The biosimilar product epoetin zeta is safe in clinical practice and is effective and stable in the weekly dose as well as in the frequency of application. Biosimilars offer a welcome opportunity to reduce treatment costs of renal anemia.

Low-flux hemodialysis suppresses interferon-gamma production: the possible role of beta2-microglobulin.

UNLABELLED: Interferon-gamma (IFN-gamma) is required for the acquired immune response involving maturation and activation of antigen-presenting cells (APC); both IFN-gamma production and activation of APC are impaired in ESRD patients on low-flux hemodialysis (HD). High levels of uremic toxins including beta2-microglobulin (beta2M) are thought to play a role in immunosuppression. PATIENTS AND METHODS: To test this hypothesis, we conducted an A-B-A crossover study to examine the influence of high-flux HD (A) versus low-flux HD (B) in ESRD patients (n = 14) using biocompatible synthetic dialyzer membranes (Polyamix(R), Gambro, Hechingen, Germany) and ultrafiltered bicarbonate-buffered dialysis fluid. Each study period lasted 6 months and at the end of each period, Kt/V urea, plasma levels of albumin, C-reactive protein (CRP) and beta2M were determined. In addition, production of IFN-gamma induced by heat-killed Staphylococcus epidermidis (Staph epi) was performed in whole blood cultures. RESULTS: Kt/V urea (mean +/- SEM) was 1.45 +/- 0.06 in Period A, 1.36 +/- 0.07* in Period B, and 1.51 +/- 0.07 in Period A' (*p < 0.01). beta2M resting levels increased from 26.6 +/- 1.42 mg/l in Period A to 34.7 +/- 2.30* mg/l in Period B, and decreased to 21.6 +/- 1.07 mg/l at the end of Period A' (*p < 0.0001). Albumin and CRP levels did not differ significantly. Staph epi-induced IFN-gamma production was 1.2 +/- 0.39 ng/1,000 PBMC at the end of Period A, 0.34 +/- 0.10 ng/1,000 PBMC* in Period B, and 2.71 +/- 0.67 ng/1,000 PBMC at the end of Period A' (*p < 0.05). There was an inverse correlation between b2M levels and whole blood IFN-gamma production (R2 = 0.26). CONCLUSION: High levels of uremic toxins such as beta2M suppress IFN-gamma production in ESRD patients under low-flux HD. High-flux HD reduces beta2M levels by 30% and improves IFN-gamma production suggesting an improved cellular immune response in ESRD patients.

[Diabetic nephropathy and heart surgery--prevention of perioperative acute renal failure]. / Diabetische Nephropathie--Peri-/postoperative Niereninsuffizienz und ihre Prophylaxe.

The diabetic micro- and macroangiopathy leads to retinopathy, nephropathy, peripheral arteriosclerosis and coronary heart disease. Diabetic patients with identified comorbidity, such as nephropathy and peripheral arteriosclerosis, have the highest mortality after heart surgery. Long-term survival is better after coronary surgery compared to catheter angioplasty without or with stent implantation. Compared to "on-pump" surgery using a cardiopulmonary bypass, "off-pump surgery is associated with a lower incidence of acute renal failure. In order to prevent acute renal failure in the course of heart surgery in diabetic patients, the following recommendations should be followed: i) the degree of renal damage (as indicated by the parameters: creatinine-clearance, albuminuria and blood pressure) has to be known before start of surgery; ii) the volume status (central venous pressure, central venous oxygen saturation) should be controlled tightly starting 12 hours before surgery; iii) if the volume status gets out of control post surgery, intensive care treatment using dopamine or loop diuretics should be stopped after 12-24 hours in case of treatment failure; iv) reduce the dose of or better avoid nephrotoxic substances (radio contrast media, antibiotics, non-steroidal pain killers; v) start effective renal replacement therapy early (daily intermittent or continuous hemodialysis, hemofiltration or hemodiafiltration).

Life-threatening complications of extracorporeal treatment in patients with severe eosinophilia.

We report three patients with massive eosinophilia of different etiology who developed bronchoconstriction, hypotension, and shock shortly after dialysis or leukapheresis had been begun. In two cases, ethylene oxide-free materials had been used ruling out an allergic reaction related to this compound. Degranulation of eosinophils with release of eosinophil peroxidase may have caused the observed adverse reactions, as suggested by in vitro experiments with blood from the three patients. Our observations draw attention to the fact that extracorporeal therapies may initiate life-threatening complications in patients with severe eosinophilia.

Low dialysance of asymmetric dimethylarginine (ADMA)--in vivo and in vitro evidence of significant protein binding.

BACKGROUND: Increased blood levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predict cardiovascular mortality in patients with end-stage renal disease. Despite its low molecular weight, available information on the impact of hemodialysis (HD) on ADMA plasma levels is controversial. METHODS: We assessed plasma concentrations, dialyzer clearance and total amount of ADMA removed in 30 patients with end-stage renal disease during regular HD. In addition, plasma ADMA levels were assessed in 10 patients with acute renal failure treated with extended HD. RESULTS: Regular HD decreased plasma creatinine (from 774 +/- 42 to 312 +/- 17 micromol/l) and urea (from 24.5 +/- 1.5 to 8.4 +/- 0.5 mmol/l) concentrations significantly (both p < 0.001), whereas plasma ADMA remained unchanged (4.35 +/- 0.19 vs. 4.76 +/- 0.24 micromol/l). ADMA clearance was 92 +/- 6 ml/min, and the total amount removed in the spent dialysate was 37 +/- 4 micromol. The clearances of creatinine (161 +/- 3 ml/min) and of urea (173 +/- 3 ml/min) were significantly higher. Furthermore, even during extended HD, plasma ADMA concentrations did not decrease significantly (1.73 +/- 0.22 vs. 1.63 +/- 0.18 micromol/l). CONCLUSION: In conclusion, dialysance of ADMA is markedly lower than expected from its molecular weight because of significant protein binding of the substance. Since markedly increased ADMA blood concentrations have been linked to cardiovascular complications due to atherosclerosis in patients with ESRD, new strategies should be evaluated to remove this putative uremic toxin.

Interleukin-18, interleukin-18 binding protein and impaired production of interferon-gamma in chronic renal failure.

UNLABELLED: Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-gamma (IFNgamma) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. METHODS: Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40). In addition, Staphylococcus epidermidis-induced production of IFNgamma and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. RESULTS: Plasma IL-18 (mean +/- SEM) in NKF was 17.9 +/- 3.6 pg/ml, in CR142.6 +/- 7.0 pg/ml (p < 0.01), and in HD 93.5 +/- 13.6 pg/ml (p < 0.001). The level of IL-18BP in NKF was 3.4 +/- 0.4 ng/ml, in CRI 7.5 +/- 0.7 ng/ml (p < 0.001), and in HD 13.1 +/- 0.8 ng/ml (p < 0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479). The level of free IL-18 was calculated in NKF to be 13.8 +/- 3.3 pg/ml, in CRI 23.6 +/- 3.9 pg/ml (not significant), and in HD 39.6 +/- 5.9 pg/ml (p < 0.001). Stimulated whole blood production of IFNgamma in NKF was 185 +/- 74 pg/10(6) mononuclear cells (PBMC), but suppressed in HD to 27.3 +/- 16 pg/10(6) PBMC (p < 0.05). CONCLUSION: In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNgamma production in whole blood is reduced in patients on HD. Therefore, suppression of IFNgamma production in uremia may be due to inhibitors of IFNgamma production other than IL-18BP.

Effects of dialyzer membrane on interleukin-1beta (IL-1beta) and IL-1beta-converting enzyme in mononuclear cells.

BACKGROUND: In vitro stimulation of mononuclear cells (peripheral blood mononuclear cells; PBMCs) with an endotoxin (lipopolysaccharide; LPS) revealed elevated cell-associated levels of interleukin-1beta (IL-1beta) in end-stage renal disease (ESRD) patients on Cuprophan hemodialysis (HD), suggesting a defect in the process of IL-1beta's release from activated cells. IL-1beta is initially synthesized as an inactive precursor called proIL-1beta. ProIL-1beta is processed into the biologically active mature form of IL-1beta (mIL-1beta) requiring the specific IL-1beta-converting enzyme (ICE). METHODS: Using specific immunoassays (enzyme-linked immunosorbent assays), we measured cell-associated and extracellular proIL-1beta as well as mIL-1beta in LPS-stimulated PBMCs to test whether ICE-dependent processing of proIL-1beta and/or secretion of mIL-1beta was impaired in ESRD patients compared with healthy controls. PBMCs of healthy controls (N = 9), of ESRD patients on peritoneal dialysis (PD, N = 10), and of those patients on intermittent HD (N = 8) were studied. The same HD patients were studied three times with low-flux Cuprophan (GFS 12), low-flux polysulfon (F6 HPS), and high-flux polysulfon (F60S) in randomized order. PBMCs were separated from whole blood by Ficoll-Hypaque centrifugation and incubated in vitro for 18 hours in the presence LPS (10 ng/mL). Extracellular (PBMC culture supernatants) and cell-associated (cell lysates) levels of proIL-1beta and mIL-1beta were measured. RESULTS: The total production (cell-associated plus extracellular) of LPS-induced IL-1beta (proIL-1beta plus mIL-1beta) was similar in healthy controls (25.96 +/- 0.84 ng/2.5 x 10(6) PBMC), PD patients (29.53 +/- 1.31 ng/2.5 x 106 PBMC), and in Cuprophan-treated HD patients (23.28 +/- 1.24 ng/2.5 x 10(6) PBMC). In normal controls, 43.6% of the total IL-1beta was processed into mIL-1beta, which was significantly more than that in PD patients (27.3%, P < 0.02) but was similar to that in Cuprophan-treated HD patients (37.1%). Comparing cell-associated and extracellular concentrations of mIL-1beta, PBMCs of normal controls secreted 82.2% of mIL-1beta; this was significantly more than that in PD patients (59.4%, P < 0.01) and that in Cuprophan HD patients (54.2%, P < 0.01). When HD patients were switched from Cuprophan to F6 HPS or F60S, neither total IL-1beta production nor processing of IL-1beta changed. However, secretion of mIL-1beta increased significantly with F6 HPS (80.6%, P < 0.01) as well as with F60S (76.6%, P < 0.02) compared with Cuprophan. CONCLUSION: We conclude that the ability of PBMCs to produce IL-1beta in response to LPS is normal in PD patients as well as in HD patients. ICE-dependent processing of inactive proIL-1beta into biologically active mIL-1beta is reduced in PD patients, but not in HD patients. Secretion of mIL-1beta is impaired in PD and HD patients treated with Cuprophan. This impaired ability to secrete active mIL-1beta seems to be independent of ICE activity and is normalized when HD-patients are switched from Cuprophan to low- or high-flux polysulfon. Increased cell-associated levels of biologically active mIL-1beta in circulating PBMCs represent a state of inflammation that may contribute to chronic inflammatory diseases such as beta2-microglobulin amyloidosis. Replacement of Cuprophan by synthetic membranes normalizes PBMC function and reduces the state of inflammation in ESRD patients.

Pyrogen retention by highly permeable synthetic membranes during in vitro dialysis.

Pyrogen permeability of the new highly permeable synthetic membrane polyethersulfone (DIAPES) was compared to polysulfone in vitro dialysis experiments with heparinized human donor blood in the blood compartment. After sterile dialysis for 5 min, dialysate was contaminated with a culture filtrate of Pseudomonas aeruginosa using high and moderate challenge doses (Limulus assay reactivity 20,000 EU/ml and 50 EU/ml, respectively). Whole blood samples were separated from the blood compartment during the sterile (5 min) and contaminated (60 min) phases of dialysis and incubated for 6 h at 37 degrees C. Blood samples were lysed, and interleukin-1beta and tumor necrosis factor alpha were measured by specific ELISAs. Moderate dialysate contamination (50 EU/ml) did not induce detectable cytokine production in whole blood. High challenge dose (20,000 EU/ml) induced whole blood interleukin-1beta and tumor necrosis factor alpha production in the blood compartment, which was higher with DIAPES than with polysulfone after 30 min. After 60 min, membrane-dependent differences were no longer detectable. Pyrogen concentrations in the dialysate decreased with time indicating adsorption of cytokine-inducing substances to the dialyzer membrane. Pyrogens adsorbed to dialyzer membranes were resuspended during recirculation of sterile phosphate-buffered saline in the dialysate compartment and retained cytokine-inducing activity as seen from whole blood incubation experiments. DIAPES and polysulfone adsorbed pyrogens in the presence of whole blood. Pyrogen adsorption to the membrane polymer and/or to the protein coat on the membrane prevented the passage of pyrogens in the presence of moderately contaminated dialysate. High grade dialysate contamination caused breakthrough of pyrogens into the blood with DIAPES and polysulfone. In order to reduce the risk of a dialysis-dependent inflammatory response, dialysate of high bacteriological quality (ultrapure dialysate) should be mandatory.

The quality of dialysate: an integrated approach.

The role of bacterial contamination of dialysis water with respect to chronic inflammatory diseases associated with long-term hemodialysis therapy has been greatly underestimated in the last two decades. In the present article, recent multicenter studies assessing the bacteriological quality of water and dialysate are discussed. In addition, we describe that pyrogenic substances of bacterial origin derived from contaminated dialysate penetrate intact dialyzer membranes with the consequence of the induction of an inflammatory response in the patients. The influence of dialyzer membrane characteristics on the passage of bacterial substances from dialysate into blood are discussed. Reaching the patients blood, bacteria-derived substances activate circulating mononuclear cells to produce proinflammatory cytokines. Cytokines such as interleukin-1 beta and tumor necrosis factor-alpha are mediators of the acute phase response resulting in elevated levels of acute phase proteins (for example, C-reactive protein). The consequence is a state of microinflammation that may contribute to progressive inflammatory diseases in chronic renal failure such as beta2-microglobulin amyloidosis, protein catabolism, and atherosclerosis. The use of sterile dialysate reduces cytokine production and plasma levels of acute phase proteins, and may positively influence progressive inflammatory diseases in patients with end-stage renal failure.

Pyrogen retention by the Asahi APS-650 polysulfone dialyzer during in vitro dialysis with whole human donor blood.

The purpose of this study was to test the pyrogen permeability of the new Asahi polysulfone APS 650 (APS) dialyzer membrane with a high permeability for middle molecules (up to 40 kDa) in comparison with the high-flux Fresenius polysulfone F60S (F60S) membrane. Dialyzers were tested in parallel in vitro dialysis experiments with whole human donor blood in the blood compartment and contaminated bicarbonate dialysate in the dialysate compartment. Dialysate was contaminated by a filtrate (0.45 microm) of a Pseudomonas aeruginosa culture in bicarbonate dialysate. The production of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in whole blood samples taken from the in vitro dialysis system was used to detect the passage of cytokine inducing bacterial substances derived from P. aeruginosa across the two highflux polysulfone membranes. Compared with a sterile control period at the beginning of each experiment (n = 5), the TNFalpha inducing activity in the dialysate increased from (mean +/- SEM) 42 +/- 12 pg/ml to 1,288 +/- 356 pg/ml with F60S dialyzers and from 37 +/- 10 pg/ml to 928 +/- 249 pg/ml with APS dialyzers 30 minutes after the dialysate was contaminated. The IL-1beta inducing activity in the dialysate increased similarly. In the presence of this significant contamination in the dialysate, whole blood circulating in the blood compartments for 60 minutes was not stimulated to produce increased amounts of TNFalpha or IL-1beta with neither of the two tested membranes. We conclude that F60S and APS membranes are equal in their ability to prevent the passage of cytokine inducing bacterial substances from highly contaminated dialysate into the patients' blood during hemodialysis.

Extended daily veno-venous high-flux haemodialysis in patients with acute renal failure and multiple organ dysfunction syndrome using a single path batch dialysis system.

BACKGROUND: In the treatment of acute renal failure in patients with multiple organ dysfunction syndrome (MODS), continuous renal replacement therapies (CRRT) are increasingly used because of excellent volume control in the presence of improved cardiovascular stability. Patients with MODS, however, are frequently catabolic and have a high urea generation rate requiring either cost-intensive high-volume CRRT or additional intermittent haemodialysis to provide adequate clearance of small-molecular waste products. We tested the closed-loop batch haemodialysis system (called Genius((R))) for the treatment of acute renal failure in patients with MODS in the intensive care unit. METHODS: Blood flow and countercurrent dialysate flow were reduced to 70 ml/min. Thus the 75 l dialysate tank of the Genius((R)) system lasts for 18 h of extended single-path high-flux haemodialysis (18 h-HFD) using polysulphous F60 S((R)) dialysers. Blood pressure, body temperature, and venous blood temperature in the extracorporeal circuit (no heating of the dialysate), ultrafiltration rate, serum urea levels, dialyser urea clearance, and total urea removal were monitored. In addition we tested the bacteriological quality of the spent dialysate at the end of 18-h treatments. RESULTS: Twenty patients with acute renal failure and MODS were investigated. Averaged dialyser urea clearance was 59.8 ml/min (equal to 3.6 l/h or 64.8 l/day). Total removal of urea was 14.1+/-6.5 g/day keeping serum levels of urea below 13 mmol/l. Mean arterial pressure remained stable during the 18-h treatments with a mean ultrafiltration rate of 120 ml/h. The temperature in the venous blood tubing dropped by 5+/-0.5 degrees C during the 18-h treatment (0.28 degrees C/h) in the presence of unchanged core temperature in the patients. There was no bacterial growth in 2.5 l of spent dialysate (<0.0004 colony forming units/ml). CONCLUSIONS: Extended high-flux dialysis using the Genius((R)) system combines the benefits of CRRT (good cardiovascular stability, sterile dialysate) with the advantages of intermittent dialysis (high urea clearance, low treatment costs). High efficiency, simplicity and flexibility of the system offers the unique opportunity to use the same dialysis machine for extended time periods (18 h) as well as for shorter intermittent renal replacement therapy in critically ill patients.

Chronic inflammation in hemodialysis: the role of contaminated dialysate.

Routine sodium bicarbonate-buffered dialysate is contaminated with predominantly gram-negative micro-organisms. These bacteria release pyrogenic substances such as endotoxins, peptidoglycans, exotoxins and fragments thereof. Pyrogens derived from contaminated dialysate either alone or in costimulation with activated complement components are the most important activators of circulating mononuclear cells in patients on chronic intermittent hemodialysis. Activated mononuclear cells release proinflammatory cytokines which are key mediators in acute and chronic inflammatory diseases associated with long-term hemodialysis therapy. Recent experimental and clinical data suggest that the use of pyrogen-free dialysate prevents activation of mononuclear cells and improves the state of chronic inflammation, as indicated by decreased plasma levels of C-reactive protein in chronic hemodialysis patients. Future clinical studies have to prove whether the use of pyrogen-free dialysate in combination with biocompatible dialyzer membranes and tubings reduces the incidence and severity of chronic inflammatory diseases (beta(2)-microglobulin amyloidosis, muscle protein wasting, atherosclerosis) in long-term hemodialysis patients.

Use of adsorptive mechanisms in continuous renal replacement therapies in the critically ill.

The pathophysiology of sepsis is becoming a more complicated scenario. In sepsis, endotoxin or other gram-positive derived products induce a complex and dynamic cellular response giving rise to several mediators known to be relevant in the pathogenesis of septic shock, such as specific mediators. substances responsible for up- or down-regulation of cytokine receptors and cytokine antagonists, inactivators of nuclear factor-kappaB or signal transduction pathways, and precursor molecules. In this article, we delve into some new concepts stemming from the use of sorbents in continuous plasma filtration. The rationale is based on the assumption that the nonspecific removal of several mediators of the inflammatory cascade and cytokine network may improve outcome in a rabbit model of septic shock and hemodynamics in a pilot clinical study. The importance of looking for innovative treatments specifically targeted for the special needs of the critically ill patients rather than using concepts and technology applied to the treatment of chronic renal failure is underlined.

Tumor necrosis factor-alpha during continuous high-flux hemodialysis in sepsis with acute renal failure.

UNLABELLED: Suppressed ex vivo endotoxin (ET)-induced production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), in isolated mononuclear cells (PBMCs) is associated with fatal outcome in severe sepsis. PBMCs from surviving patients, but not those from nonsurviving patients, recover their capacity to produce normal amounts of TNF-alpha. We tested the influence of two modalities of continuous renal replacement therapy (CRRT) on ex vivo-induced whole-blood production of TNF-alpha and inhibitory TNF-soluble receptor type I (TNFsRI) in 12 patients with acute renal failure and sepsis (APACHE II score 22 to 30). METHODS: Standard continuous venovenous hemofiltration (CVVH; 36 liters of bicarbonate substitution fluid per day) was performed in 7 patients using polyamid hemofilters (FH66; Gambro). In an additional five patients, we performed daily 18 hours of high-flux hemodialysis (CHFD) using polysulfon F60S dialyzers (Fresenius) and 75 liters of bicarbonate dialysate using the GENIUS single-pass batch dialysis system. Samples were separated from the blood circuit as well as from the ultrafiltrate/spent dialysate lines at the start, during, and end of treatment. Whole-blood samples were incubated with 1 ng/ml of ET for three hours at 37 degrees C. Ultrafiltrate or dialysate samples were incubated with donor whole blood in the presence of ET to measure suppressing activity in ultrafiltrate and spent dialysate. RESULTS: At the start of CRRT, ET-induced whole-blood TNF-alpha production was suppressed to approximately 10% of that in normal controls. During CVVH, median ET-induced TNF-alpha production increased from 0.35 ng/ml at the start to 1.2 ng/ml at three hours, but decreased to pre-CVVH levels at the end of a 24-hour period. In contrast, in patients on CHFD, the median ET-induced TNF-alpha production was 0.5 ng/ml at the start, 1.1 ng/ml at 3 hours, 1.6 ng/ml at six hours, and 1.5 ng/ml at the end of 18 hours of treatment. The ultrafiltrate obtained after three hours of CVVH did not contain suppressing activity. In CHFD, the spent dialysate as compared with fresh dialysate suppressed ET-induced TNF-alpha production in donor blood by 33% throughout the 18 hours of treatment. Whole-blood production of TNFsRI did not change significantly at any time point during CVVH or CHFD. CONCLUSION: These data suggest that high-volume CHFD is superior to standard CVVH in removing a suppressing factor of proinflammatory cytokine production. As CVVH only transiently improves TNF-alpha production, it is most likely that the putative suppressing factor is removed because of saturable membrane adsorption in CVVH. In CHFD, there is a combination of adsorption and detectable diffusion into the dialysate. It remains to be shown whether a further increase in the volume of dialysate per day is able to not only improve but normalize the cytokine response and improve outcome in septic patients with acute renal failure.