Background Malnutrition and chronic systemic inflammatory response syndrome not only coexist in uraemia, but may also have a bi-directional cause-and-effect relationship. To evaluate the role of dialysate-related cytokine induction in inflammatory response and nutritional status, we conducted a prospective comparison of two dialysis fluids differing in their microbiological quality. Methods Forty-eight early haemodialysis patients were assigned to either treatment with conventional (potentially microbiologically contaminated) or on-line produced ultrapure dialysis fluid. Study parameters were bacterial growth, markers of systemic inflammation (C-reactive protein (CRP) and interleukin 6), and parameters of nutritional status (estimated dry weight, upper mid-arm muscle circumference, serum albumin concentration, insulin-like growth factor 1, leptin, and protein catabolic rate). Patients were followed for 12 months. Results There were no statistically significant differences in demographic and treatment characteristics, degree of bacterial contamination of the dialysate, markers of systemic inflammation, or parameters of nutritional status among the two treatment groups at recruitment. Changing from conventional to ultrapure dialysis fluid reduced significantly the levels of IL-6 (19+/-3 pg/ml to 13+/-3 pg/ml) and CRP (1.0+/- 0.4 mg/dl to 0.5+/-0.2 mg/dl), and resulted in significant increases in estimated dry body weight, mid-arm muscle circumference, serum albumin concentration, levels of the humoral factors, and in protein catabolic rate after 12 months. Continuous use of conventional dialysis fluid (median 40-60 c.f.u./ml) was not associated with significant alterations in markers of inflammation (IL-6 21+/-4 pg/ml vs 24+/-6 pg/ml, CRP 0.9+/-0.3 mg/dl vs 1.1+/-0.4 mg/dl) or of nutritional status at any time of the study. All differences in systemic inflammation and nutritional parameters observed during the study period (from recruitment to month 12) were significant between the two patient groups. Conclusions Cytokine induction by microbiologically contaminated dialysis fluid has a negative impact on nutritional parameters of early haemodialysis patients. The microbiological quality of the dialysis fluid represents an independent determinant of the nutritional status in addition to known factors, such as dose of dialysis and biocompatibility of the dialyser membrane. Ultrapure dialysis fluid adds to the cost of the dialytic treatment, but may improve the nutritional status in long-term haemodialysis patients.

/pdf/effects-of-ultrapure-dialysis-fluid-on-nutritional-status-32ryng15px.pdf

Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters

Background: Controlled randomised studies to prove improved cardiovascular stability and improved anaemia management during on-line haemodiafiltration (oHDF) are scarce. Me

/pdf/on-line-haemodiafiltration-versus-haemodialysis-stable-3yiwifd1n0.pdf

On-Line Haemodiafiltration versus Haemodialysis: Stable Haematocrit with Less Erythropoietin and Improvement of Other Relevant Blood Parameters

Atubular glomeruli (AG) have been described in several renal disorders. However, little attention has been paid to AG in diabetic nephropathy (DN). Preliminary studies suggested that tip lesions were frequently present in type 1 diabetic (D) patients with proteinuria. The aim of this study was to determine the frequency of AG and their possible relationship with tip lesions in DN. Renal biopsies from eight proteinuric type 1 D patients with normal to moderately reduced GFR (76 +/- 26 ml/min per 1.73 m(2)) and eight normal subjects were studied by light (LM) and electron microscopy (EM). Glomerular volume, volume of the glomerular corpuscle, which is tuft, and the fractional volumes of proximal, distal, and atrophic tubules per cortex were estimated using appropriate stereologic methods. Glomerulotubular junctions were examined on serial sections and classified into glomeruli attached to: normal tubules (NT); short atrophic tubules (SAT); long atrophic tubules (LAT); atrophic tubules with no observable glomerular opening (ATNO); and atubular glomeruli (AG). EM studies showed typical diabetic changes in biopsies, including increased GBM width (P < 0.00001) and mesangial fractional volume (P < 0.0001) and decreased filtration surface density (P < 0.01) compared with normal subjects. Seventeen percent of glomeruli in the D patients were atubular, and 51% were attached to atrophic tubules. Tip lesions were present in all SAT, 64% of LAT, 82% of ATNO, and only 9% of NT and were never observed in normal subjects. The relative volume of AG was smaller than glomeruli in other categories (P < 0.05). Fractional volume of proximal (P < 0.01) and distal (P <0.01) tubules per cortex were decreased, while fractional volume of cortical interstitium (P <0.00001) and atrophic tubules (P <0.01) were increased in D patients. Fractional volume of atrophic tubules, %AG, and percent of glomeruli with tip lesion explained 94% of the GFR variability in diabetic patients (P <0.05). Thus, AG and glomerulotubular junction abnormalities may be important in the development and progression of DN.

Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy

https://www.kidney-international.org/article/S0085-2538(15)30278-7/pdf

Online hemodiafiltration reduces systemic inflammation compared to low-flux hemodialysis

As the kidney is the major site for elimination of many cytokines, the delicate equilibrium of pro-inflammatory cytokines and their inhibitors is clearly dysregulated in chronic kidney disease (CKD) p

/pdf/cytokine-dysregulation-in-chronic-kidney-disease-how-can-we-13n0iscoxs.pdf

Cytokine Dysregulation in Chronic Kidney Disease: How Can We Treat It?

Background. Microbial contamination is Conclusion. On-line HDF treatment can routinely be provided with ultra-pure dialysis fluids and sterile characterized not only by the presence of bacteria, but substitution fluids at pyrogen-free levels. The on- also by high concentrations of biologically active line preparation of substitution fluids thus can be by-products. They are potentially able to cross ultrafil- considered microbiologically safe. tration and dialysis membranes and stimulate immuno- competent blood cells to synthesize cytokines. In turn, cytokine induction causes acute symptoms and has been incriminated in the long-term complications of Introduction haemodialysis patients. Infusion of large volumes of substitution fluids following ultrafiltration of micro- Dialysis fluids, as well as their components, purified bially contaminated dialysis fluids may place patients water and dialysis concentrates, are subject to micro- on on-line therapies at particular risk. bial contamination. Indeed, poor microbiological qual- Methods. In this study we evaluated 30 machines with ity is evident in hydraulic dialysis systems, as recent a two-stage ultrafiltration system in routine clinical surveys have revealed high levels of micro-organisms haemodiafiltration settings in six centres for 6 months. in water and dialysis fluids (1-3). In turn, contamina- Microbiological safety was assessed monthly and tion with bacteria has been demonstrated to be associ- at the last use of the filters by determining micro- ated with the presence of soluble, pyrogenic (pro- bial counts, endotoxin concentration and cytokine- inflammatory cytokine-inducing) by-products, which inducing activity. are potentially able to penetrate low- and high-flux Results. No pyrogenic episodes were observed during dialysis membranes alike (4,5). As a consequence, the study period. Double-filtration of standard dialysis haemodialysis (HD) patients exhibit chronic inflam- fluid (range, <1-895 cfu/ml, 0.0028-4.6822 IU/ml ) mation, an increasingly unravelled factor of long-term resulted in sterile substitution fluids with endotoxin morbidity and mortality (6-9). In addition, acute concentrations well below the Ph.Eur. standard for febrile reactions may be triggered by excessive trans- haemofiltration solutions (range, 0.0014-0.0281 vs 0.25 membrane passage of cytokine-inducing substances IU/ml ). Moreover, they did not differ from commercial (10,11). haemofiltration solutions and depyrogenated saline. Highly convective therapies in their most practical Likewise, there was no difference in the cytokine- and cost-effective form include a large volume substitu- inducing activity between the solutions tested. The tion with on-line prepared infusates. Substitution with high microbiological quality of the ultrafiltered dialysis fluid prepared from contaminated dialysate, however, fluid, which was in the same range as substitution may place patients at particular risk with respect to fluid, translates into both the absence of cytokine pyrogen exposure. The high retention capabilities of induction by dialyser back-transport and a redundant ultrafilters to micro-organisms and endotoxins in the safety mode of the on-line system by a second filtra- laboratory or clinical setting suggest the micro- tion step.

/pdf/can-sterile-and-pyrogen-free-on-line-substitution-fluid-be-4dpbg7h92y.pdf

Can sterile and pyrogen-free on-line substitution fluid be routinely delivered? A multicentric study on the microbiological safety of on-line haemodiafiltration.

: Background: On-line hemodiafiltration (HDF) represents the supreme blood purification modality for end-stage renal disease (ESRD) patients. Large-volume infusion of on-line prepared substitution fluid may, however, expose patients to inflammatory contaminants. As a result, on-line HDF might aggravate chronic inflammation, which correlates with malnutrition, cardiovascular disease, and mortality among ESRD patients. Methods: In a multicenter cross-over study, 27 ESRD patients were randomly assigned to treatment with on-line HDF and low-flux hemodialysis (HD). After 6 months, patients were crossed to the other treatment modality, and treatment continued for another 6 months. Both on-line HDF and low-flux HD were conducted with polysulfone membranes and ultrapure dialysis fluid. Samples were drawn at the end of each treatment period. Results: Inflammatory parameters were elevated in the study population when compared to healthy controls. Induction of interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor α (TNF-α) was comparable for on-line HDF and low-flux HD, and there was no intradialytic increase in cytokine production. As a result, interleukin-6 (IL-6) plasma levels did not differ significantly between the two treatment modalities. Similarly, no difference between on-line HDF and low-flux HD was observed for C-reactive protein (CRP) and albumin. Markers of endothelial cell activation (soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1) as well as the cardiovascular risk marker cardiac troponin T (cTnT) remained elevated compared to healthy subjects, but showed no difference between the two treatment modalities. Conclusions: On-line HDF, as the most effective renal replacement therapy, does not provoke inflammatory response and is both safe and highly biocompatible.

On‐line Hemodiafiltration Does Not Induce Inflammatory Response in End‐stage Renal Disease Patients: Results From a Multicenter Cross‐over Study

Cost reduction and quality improvement seem to be conflicting issues. However, online hemodiafiltration (oHDF) with new automatic functions offers a cost-efficient therapy compared to hemodialysis (HD). Seven dialysis centers conducted a randomized clinical trial with cross-over design: high-flux HD vs. postdilutional oHDF with functions coupling both dialysate and substitution flow rates to blood flow rates. During the 6 weeks of the study, all treatment parameters remained unchanged for HD and oHDF, apart from dialysate and substitution flow rate. Treatment data were recorded during each treatment, and predialytic and postdialytic concentrations of urea were recorded at the end of each study phase. The analysis involved 956 treatments of 54 patients. The mean dialysate consumption was 123.2 ± 6.4 l for HD and 113.4 ± 14.9 l for oHDF (p < 0.0001), the mean dialysis dose was 1.42 ± 0.23 for HD and 1.47 ± 0.26 for oHDF (p < 0.0001); oHDF resulted in a lower dialysate consumption (8.0% less) and a slightly increased dialysis dose (Kt/V 3.5% higher) compared to HD. oHDF with the investigated automatic functions offers substantial savings in dialysate consumption without decreasing dialysis dose.

Dialysate saving by automated control of flow rates: comparison between individualized online hemodiafiltration and standard hemodialysis.

End-stage renal disease (ESRD) patients are known to suffer from chronic inflammation as the result of an ongoing subacute cytokine induction, which may contribute considerably to dialysis-related, long-term morbidity and mortality. Preparation of infusate from cytokine-inducing dialysis fluid and its administration in large quantities as well as the use of high-flux membranes bear the risk of aggravating the chronic inflammatory response among online hemodiafiltration (online HDF) patients. In order to assess the inflammatory risk associated with online HDF, we compared the cytokine induction profile of ESRD patients receiving either online HDF or low-flux hemodialysis (low-flux HD). Specifically, we measured spontaneous and lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNFalpha) and interleukin-1 receptor antagonist (IL-1Ra) release during ex vivo incubation of whole blood. Ultrapure dialysis fluid and polysulfone membranes were used for both treatment modalities. LPS-stimulated release of TNFalpha and IL-1Ra was elevated for both online HDF and low-flux HD patients compared to healthy individuals (TNFalpha: 2,336 +/- 346 and 2,192 +/- 398 versus 1,218 +/- 224 pg/106 white blood cells [WBC]; IL-1Ra: 2,410 +/- 284 and 2,326 +/- 186 versus 1,678 +/- 219 pg/106 WBC). Likewise, spontaneous production of TNFalpha, but not IL-1Ra, was higher in online HDF and low-flux HD patients than in normal controls (37 +/- 32 and 22 +/- 19 versus 0.8 +/- 0.3 pg TNFalpha/106 WBC). There was no difference in spontaneous and LPS-stimulated cytokine release between both dialysis groups. In addition, intradialytic cytokine induction was not significant for either treatment modality as spontaneous and LPS-stimulated cytokine release were not increased postdialysis. These findings indicate that online HDF does not contribute to chronic leukocyte activation and, consequently, does not place ESRD patients at greater risk with respect to inflammatory morbidity and mortality.

Cytokine Induction in Patients Undergoing Regular Online Hemodiafiltration Treatment

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Papers

Can sterile and pyrogen-free on-line substitution fluid be routinely delivered? A multicentric study on the microbiological safety of on-line haemodiafiltration.

On‐line Hemodiafiltration Does Not Induce Inflammatory Response in End‐stage Renal Disease Patients: Results From a Multicenter Cross‐over Study

Dialysate saving by automated control of flow rates: comparison between individualized online hemodiafiltration and standard hemodialysis.

Cytokine Induction in Patients Undergoing Regular Online Hemodiafiltration Treatment