Uremia impairs blood dendritic cell function in hemodialysis patients
2007; Elsevier BV; Volume: 71; Issue: 11 Linguagem: Inglês
10.1038/sj.ki.5002196
ISSN1523-1755
AutoresWai H. Lim, Svjetlana Kireta, Graeme R. Russ, Patrick T. Coates,
Tópico(s)Immunotherapy and Immune Responses
ResumoPatients on hemodialysis have a general immunodeficiency involving both innate and adaptive responses. As the mechanisms contributing to this defect are uncertain, we sought to study the effects of uremia on circulating dendritic cells (DC) in hemodialysis patients. Immunomagnetic beads were used to isolate myeloid and plasmacytoid DCs from healthy donors. Immune-related functions were determined in these cells cultured in either a complete media containing ABO-compatible serum or media containing sera from uremic patients. The myeloid cells were analyzed for costimulatory molecule expression and allo-stimulatory capability following lipopolysaccharide stimulation. The production of interferon-α following herpes-simplex virus stimulation by the plasmacytoid cells was also measured. Myeloid DCs incubated with uremic sera demonstrated impaired maturation and decreased allo-stimulatory capacity. Similarly, herpes virus-stimulated plasmacytoid DCs incubated with uremic sera produced significantly less interferon-α compared with cells incubated in the complete media. Both small and large molecule uremic toxins inhibited DC functions in vitro. Use of more efficient dialysis to improve small molecule clearance reversed the inhibition of uremic sera on myeloid but not plasmacytoid DC function. We have shown that the immunodeficiency of hemodialysis patients is due to dialyzable uremic toxins. Patients on hemodialysis have a general immunodeficiency involving both innate and adaptive responses. As the mechanisms contributing to this defect are uncertain, we sought to study the effects of uremia on circulating dendritic cells (DC) in hemodialysis patients. Immunomagnetic beads were used to isolate myeloid and plasmacytoid DCs from healthy donors. Immune-related functions were determined in these cells cultured in either a complete media containing ABO-compatible serum or media containing sera from uremic patients. The myeloid cells were analyzed for costimulatory molecule expression and allo-stimulatory capability following lipopolysaccharide stimulation. The production of interferon-α following herpes-simplex virus stimulation by the plasmacytoid cells was also measured. Myeloid DCs incubated with uremic sera demonstrated impaired maturation and decreased allo-stimulatory capacity. Similarly, herpes virus-stimulated plasmacytoid DCs incubated with uremic sera produced significantly less interferon-α compared with cells incubated in the complete media. Both small and large molecule uremic toxins inhibited DC functions in vitro. Use of more efficient dialysis to improve small molecule clearance reversed the inhibition of uremic sera on myeloid but not plasmacytoid DC function. We have shown that the immunodeficiency of hemodialysis patients is due to dialyzable uremic toxins. Infectious complications are a common cause of morbidity and mortality in end-stage renal disease (ESRD) patients maintained on renal replacement therapies (e.g. hemodialysis (HD)).1.McDonald S. Deaths ANZDATA Registry Report 2003.in: McDonald S. Russ G.R. Australia and New Zealand Dialysis and Transplant Registry. Adelaide, South Australia2003: 19Google Scholar,2.U.S. Renal Data System: USRDS 1998 annual data report.Am J Kidney Dis. 1998; 32: 9-162PubMed Google Scholar In addition, ESRD patients often have a poor response to vaccinations (e.g. hepatitis B) achieving low therapeutic antibody titres,3.Kohler H. Arnold W. Renschin G. et al.Active hepatitis B vaccination of dialysis patients and medical staff.Kidney Int. 1984; 25: 124-128Abstract Full Text PDF PubMed Scopus (145) Google Scholar and have a higher risk of malignancies.4.Matas A. Simmons R. Kjellstrand C. et al.Increased incidence of malignancy during chronic renal failure.Lancet. 1975; 1: 883-886Abstract PubMed Scopus (291) Google Scholar These observations suggest an underlying generalized defect in both innate and adaptive immunity, but the underlying mechanisms remain unclear.5.Girndt M. Sester M. Sester U. et al.Molecular aspects of T- and B-cell function in uremia.Kidney Int. 2001; 78: S206-S211Crossref Google Scholar Dendritic cells (DC) are unique professional antigen-presenting cells that coordinate both innate and adaptive arms of the immune system.6.Banchereau J. Briere F. Caux C. et al.Immunobiology of dendritic cells.Ann Rev Immunol. 2000; 18: 767-811Crossref PubMed Scopus (5614) Google Scholar DC are critical in stimulating effector cells (including naïve T cells and natural killer cells) in response to captured foreign antigens.7.Inaba K. Inaba M. Naito M. Steinman R. Dendritic cell progenitors phagocytose particulates, including Bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo.J Exp Med. 1993; 23: 1595-1601Google Scholar There are at least two distinct subsets of circulating DC precursors derived from CD34+ bone-marrow hematopoietic progenitor cells in the peripheral blood (PB). These include precursor myeloid and precursor plasmacytoid DC,8.O'Doherty U. Peng M. Gezelter S. et al.Human blood contains two subsets of dendritic cells, one immunologically mature, and the other immature.Immunology. 1994; 82: 487-493PubMed Google Scholar, 9.Liu Y. Kanzler H. Soumelis V. Gilliet M. Dendritic cell lineage, plasticity and cross-regulation.Nat Immunol. 2001; 2: 585-589Crossref PubMed Scopus (532) Google Scholar, 10.Robinson S. Patterson S. English N. et al.Human peripheral blood contains two distinct lineages of dendritic cells.Eur J Immunol. 1999; 29: 2769-2775Crossref PubMed Scopus (323) Google Scholar which can be easily identified and isolated by flow cytometric cell sorting or via immunomagnetic bead separation technique.11.Olweus J. BitMansour A. Warnke R. et al.Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin.Proc Natl Acad Sci USA. 1997; 94: 12551-12556Crossref PubMed Scopus (391) Google Scholar,12.Dzionek A. Fuchs A. Schmidt P. et al.BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood.J Immunol. 2000; 165: 6037-6046Crossref PubMed Scopus (1065) Google Scholar Precursor myeloid DC (MDC) are derived from myeloid precursors, express CD11c and blood dendritic cell antigen (BDCA)-1 (CD1c).12.Dzionek A. Fuchs A. Schmidt P. et al.BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood.J Immunol. 2000; 165: 6037-6046Crossref PubMed Scopus (1065) Google Scholar These cells are immunosurveillant cells and drive a potent T-helper (Th) 1-type polarized immune response to lipopolysaccharide (LPS).9.Liu Y. Kanzler H. Soumelis V. Gilliet M. Dendritic cell lineage, plasticity and cross-regulation.Nat Immunol. 2001; 2: 585-589Crossref PubMed Scopus (532) Google Scholar Plasmacytoid DC (PDC) are a recently described DC subset that express cell-surface markers CD123, BDCA-2 and 4.12.Dzionek A. Fuchs A. Schmidt P. et al.BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood.J Immunol. 2000; 165: 6037-6046Crossref PubMed Scopus (1065) Google Scholar PDC are critical in antiviral and possibly antitumour immunity by producing large amounts of type I-interferon (IFN).13.Cella M. Facchetti F. Lanzavecchia A. Colonna M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent Th1 polarization.Nat Immunol. 2000; 1: 305-310Crossref PubMed Scopus (685) Google Scholar, 14.Liu Y. IPC: Professional type I interferon-producing cells and plasmacytoid dendritic cell precursors.Annu Rev Immunol. 2005; 23: 275-306Crossref PubMed Scopus (1323) Google Scholar, 15.Bauer M. Redecke V. Ellwart J. et al.Bacterial CpG-DNA triggers activation and maturation of human CD11c-, CD123+ dendritic cells.J Immunol. 2001; 166: 5000-5007Crossref PubMed Scopus (275) Google Scholar The effect of renal failure on DC function has not been extensively investigated. In a previous study, we established that immunomagnetic bead isolated uremic MDC and PDC from HD patients were functionally impaired ex vivo with reduced cell-surface costimulatory molecule expression and IFN-α production following appropriate stimulation.16.Lim W.H. Kireta S. Russ G.R. Coates P.T.H. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients.Transplantation. 2006; 81: 160-168Crossref PubMed Scopus (37) Google Scholar We hypothesized that uremic toxins accumulated at high concentrations in the sera of HD patients inhibit blood DC functions in vivo. In this study, we assessed the impact of uremic sera of HD patients on MDC and PDC functions in vitro. We demonstrate that uremic toxins of all molecular weights (MWs) contained within the sera of HD patients inhibit DC function, and that these effects are potentially reversable by more efficient dialysis. Our findings provide a rationale for utilizing HD regimens to improve clearance of uremic toxins and enhance overall immune function in HD patients. Serum interleukin (IL)-12p70 levels were significantly higher in HD patients (n=12, 43.1±11.0 pg/ml) compared with healthy controls/human AB serum (n=14, below level of detection; Mann–Whitney U-test P 10 separate HD patients; Figure 1a). These findings translated to a significantly reduced allo-stimulatory capacity in mixed lymphocyte reaction (sera of five separate HD patients, Mann–Whitney U-test P 10 separate HD patients, mean fluorescent intensity (MFI) 5.3±3.8 compared with 10.6±6.8, respectively, P=not statistically significant (NS)), but similar proportion of annexin and/or propidium iodide (PI)-positive cells (sera of three separate HD patients, 49.8±13.2% compared with 57.2±10.4% of total cells, respectively, P=NS). LPS-stimulated BDCA-1+ MDC cultured in UM compared with CM produced a greater amount of IL-12p70 (sera of >10 separate HD patients, 58.9±10.4 pg/ml compared with 25.2±5.2 pg/ml, Mann–Whitney U-test P<0.01). The amount of IL-12p70 present in CM and UM was below level of detection and 9.2±4.5 pg/ml, respectively (Mann–Whitney U-test P<0.01). These experiments represent the use of between 3 and 6 healthy blood donors' cells. We next sought to determine the effect of different MW uremic toxins on BDCA-1+ MDC functions. Increasing concentrations of urea were added to CM containing normal BDCA-1+ MDC in quantities comparable to ESRD patients. Increasing concentrations of urea imparted a dose-dependent inhibition of the ability of LPS-stimulated normal BDCA-1+ MDC to upregulate costimulatory molecule/CD83 (representative of six experiments; Figure 2a–d) and allogeneic T-cell proliferation (representative of three experiments, normal BDCA-1+ MDC cultured in the presence of urea 40 mmol/l induced significantly less T-cell proliferation compared with cells cultured in CM and lower concentrations of urea, Kruskal–Wallis test P=0.04; Figure 2e). The amount of IL-12p70 produced by LPS-stimulated normal BDCA-1+ MDC cultured in CM (18.8±7.5 pg/ml) was greater than the amount produced by cells cultured in the presence of urea 5 mmol/l (12.4±5.8 pg/ml), 20 mmol/l (2.1±0.3 pg/ml), and 40 mmol/l (0.5±0.2 pg/ml, Kruskal–Wallis test P<0.01, representative of six experiments). CD95 expression (data not shown) and the proportion of annexin±PI-positive LPS-stimulated normal BDCA-1+ MDC cultured in CM±urea was similar (49.8±13.2% compared with 57.2±10.4% of total cells, respectively, P=NS, representative of six experiments). These experiments represent the use of six healthy blood donors' cells. We next evaluated the effect of small/middle- ( 5000 Da) toxins on normal BDCA-1+ MDC function. Similar to the effect of 40 mmol/l of urea in CM, both uremic serum fractions inhibited the ability of LPS-stimulated normal BDCA-1+ MDC to express costimulatory molecules and CD83 (sera of three separate HD patients; Figure 3) and significantly inhibited allogeneic T-cell proliferation (sera of three separate HD patients; Figure S1, Kruskal–Wallis test P=0.002). LPS-stimulated normal BDCA-1+ MDC cultured in the presence of small/medium- and large MW uremic serum fractions produced significantly less IL-12p70 compared with BDCA-1+ MDC cultured in CM (7.1±5.2, 5.1±0.3 and 25.3±6.1 pg/ml, respectively, Kruskal–Wallis test P<0.01, sera of three separate HD patients). The amount of IL-12p70 present in CM and in small/medium and large MW uremic serum fractions were below the level of detection. CD95 expression (data not shown) and the proportion of annexin±PI-positive LPS-stimulated BDCA-1+ MDC cultured in the presence of either uremic serum fractions were comparable with cells cultured in CM (34.7±19.2 compared with 41.2±21.3% of total cells, respectively, P=NS, sera of three separate HD patients). These experiments represent the use of three healthy blood donors' cells. Download .jpg (.03 MB) Help with files Supplementary Figure 1 Freshly isolated uremic BDCA-1+ MDC from HD patients exhibited reduced fluorescein isothiocyanate (FITC)-dextran uptake compared with normal BDCA-1+ MDC (representative of three separate HD patients, MFI 33.3±8.1 and 2.3±1.9, respectively, Student's t-test P<0.01; Figure 4). Following LPS stimulation, uremic BDCA-1+ MDC cultured in CM or autologous UM demonstrated impaired expression of costimulatory molecules and CD83 (representative of three separate HD patients; Figure S2). The proportion of trypan blue staining dead uremic BDCA-1+ MDC cultured in CM or autologous UM was similar (25±12 compared with 28±9% of total BDCA-1+ MDC, respectively, P=NS). Download .jpg (.05 MB) Help with files Supplementary Figure 2a LPS-stimulated uremic BDCA-1+ MDC cultured in UM compared with CM produced greater amounts of IL-12p70 (54.2±10.2 compared with 1.2±0.1 pg/ml, Student's t-test P<0.001, representative of three separate HD patients). The amount of IL-12p70 in UM and CM was 9.2±2.1 pg/ml and below the level of detection, respectively. As with normal BDCA-1+ MDC cultured in UM, uremic BDCA-1+ MDC cultured in CM or autologous UM exhibited minimal allo-stimulatory capacity compared with normal BDCA-1+ MDC cultured in CM (representative of three separate HD patients, Kruskal–Wallis test P=0.003; Figure 5). Herpes-simplex virus-1 (HSV-1)-stimulated normal BDCA-4+ PDC cultured in UM produced significantly less IFN-α than PDC cultured in CM (53.8±7.8 compared with 2000±183.2 pg/ml, Student's t-test P<0.001, sera of three separate HD patients). The proportion of trypan blue staining dead normal BDCA-4+ PDC cultured in CM or UM was similar (31±9 compared with 35±12% of total cells, respectively, P=NS), indicating that cell death did not account for the reduction in cytokine secretion. We next sought to determine which components of uremic serum might explain the inhibitory effects on BDCA-4+ PDC function. Compared with HSV-1-stimulated normal BDCA-4+ PDC in CM (2000±183.2 pg/ml) or in the presence of 5 mmol/l of urea in CM (1642±218.3 pg/ml), the presence of 20 mmol/l (102.1±10.5 pg/ml) and 40 mmol/l (54.1±14.2 pg/ml) of urea in CM, (representative of three separate experiments) or both small/middle- (32.1±4.4 pg/ml) and large MW (<10 pg/ml) uremic serum fractions (sera of three separate HD patients) inhibit IFN-α production (Kruskal–Wallis test P<0.001). Again, the proportion of trypan blue staining dead cells was similar in all experiments (data not shown, P=NS). These experiments represent the use of nine healthy blood donors' cells. We have previously shown that the ability of HSV-1-stimulated uremic BDCA-4+ PDC from HD patients cultured in CM and autologous UM to produce IFN-α was profoundly reduced (47.1±17.4 and 33.2±8.7 pg/ml compared with 2000±4.5 pg/ml produced by normal BDCA-4+ PDC, Kruskal–Willis test P<0.001, uremic PDC representative of three HD patients).16.Lim W.H. Kireta S. Russ G.R. Coates P.T.H. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients.Transplantation. 2006; 81: 160-168Crossref PubMed Scopus (37) Google Scholar The proportion of trypan blue-staining dead uremic BDCA-4+ PDC cultured in CM and autologous UM was similar (28±10 and 33.1±14% of total cells, respectively, P=NS) suggesting that our results were not indicative of reduced PDC numbers. To assess whether more efficient dialysis to remove uremic toxins reverses the inhibitory effects of uremic serum on DC functions, the effect of uremic sera of two HD patients maintained on polyflux membrane on normal BDCA-1+ MDC and BDCA-4+ PDC function was analyzed. The levels of IL-12p70 detected in the sera of HD patients maintained on polyflux membranes were slightly reduced compared with the levels pre-membrane change (i.e. maintained on polysulfone membrane; 19.1±3.5 compared with 21.1±6.5 pg/ml, P=NS). LPS-stimulated normal BDCA-1+ MDC cultured in UM (polyflux membrane) displayed appropriate expression of costimulatory molecule and CD83 (sera of two HD patients used; Figure S3) and allogeneic T-cell proliferation compared with cells (from the same blood donor) cultured in UM containing serum from the same HD patient maintained on polysulfone membrane (sera of two HD patients used; Figure S4, P=NS). IL-12p70 production by LPS-stimulated normal BDCA-1+ MDC cultured in UM containing serum from the same HD patient obtained pre- and post membrane change was similar (60.2±10.4 and 67.2±19.2 pg/ml, respectively, P=NS, sera of two HD patients). The amount of IL-12p70 in both UM was similar (9.3±2.3 and 10.2±5.2 pg/ml, P=NS). CD95 expression and the proportion of annexin and/or PI-positive cells were comparable (32±12 and 29.4±9% of total cells, respectively, P=NS). Download .jpg (.07 MB) Help with files Supplementary Figure 3 Download .jpg (.04 MB) Help with files Supplementary Figure 4 In contrast, normal BDCA-4+ PDC cultured in UM containing serum from the same HD patient obtained pre- (polysulfone) or post-membrane (polyflux) change demonstrated impaired production of IFN-α compared with cells cultured in CM (70.1±14.3, 59.4±19.2, and 500±4.5 pg/ml, respectively, Kruskal–Willis test P<0.001). The proportion of trypan blue-staining dead normal BDCA-4+ PDC cultured in medium containing the different sera was similar and comparable to CM-cultured cells (37±15 and 40.1±11% of total cells, respectively, P=NS). These experiments represent the use of four healthy blood donors' cells. We next investigate whether enhanced dialysis with polyflux membrane translated to an improvement in the intrinsic function of uremic BDCA-1+ MDC ex vivo. In the same two HD patients, uremic BDCA-1+ MDC isolated 2 months following the conversion from polysulfone to polyflux membrane exhibited improved endocytic capacity (MFI 2.3±1.9 and 17.6±4.3, respectively, Student's t-test P<0.01; Figure 4), expression of costimulatory molecule/CD83 (Figure 6a), and allogeneic T-cell proliferation (representative of one HD patient, P=NS; Figure 6b). There were no differences in the proportion of trypan blue-staining dead uremic BDCA-1+ MDC pre- and postmembrane change (25±12% compared with 20±12% of total MDC, respectively, P=NS). In these studies, we examined the mechanisms of DC dysfunction in chronic HD patients. We have previously shown that uremic blood MDC and PDC were functionally impaired,16.Lim W.H. Kireta S. Russ G.R. Coates P.T.H. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients.Transplantation. 2006; 81: 160-168Crossref PubMed Scopus (37) Google Scholar a factor likely to contribute to the higher rates of infectious complications observed in these patients. Thus, the present studies were performed to examine (1) the effect of uremic serum and its components on blood MDC and PDC functions and (2) the effect of improved dialysis clearance on DC functions in HD patients prospectively. In this study, we show that uremic sera of HD patients inhibit normal MDC and PDC functions. The presence of uremic serum impairs MDC maturation resulting in reduced allo-stimulatory capacity. Interestingly, the ability of UM-cultured MDC to produce IL-12p70 was significantly enhanced, which may reflect the well documented presence of bioactive IL-12p70 in uremic sera of HD patients.17.Memoli B. Marzano L. Bisesti V. et al.Hemodialysis-related lymphomononuclear release of interleukin-12 in patients with end-stage renal disease.J Am Soc Nephrol. 1999; 10: 2171-2176PubMed Google Scholar IL-12 is a proinflammatory cytokine that has been shown to enhance IL-12 production by DC via stimulation of the IL-12 receptor.18.Langrish C. McKenzie B. Wilson N. et al.IL-12 and IL-23: master regulators of innate and adaptive immunity.Immunol Rev. 2004; 202: 96-105Crossref PubMed Scopus (609) Google Scholar For the first time, we demonstrated that the presence of uremic serum inhibited normal PDC functions by diminishing their ability to secrete IFN-α following HSV-1 stimulation without affecting cell viability. Apoptosis of immune-regulating cells such as PB mononuclear cell (PBMC),19.Sendo F. Tsuchida H. Takeda Y. et al.Regulation of neutrophil apoptosis: its biological significance in inflammation and the immune response.Hum Cell. 1996; 9: 215-222PubMed Google Scholar monocytes,20.Heidenreich S. 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Morgan A. et al.Impaired polymorphonuclear neutrophil function in end-stage renal failure and its correction by continuous ambulatory peritoneal dialysis.Nephron. 1995; 71: 133-137Crossref PubMed Scopus (20) Google Scholar In this study, we identified that small- (represented by urea), medium- and large-MW uremic toxins within uremic serum inhibit normal MDC and PDC functions, comparable to the effects of uremic serum on these cells. However, it is possible that drugs including vitamin D analogues such as calcitriol are present within the sera of HD patients, which may also contribute to the inhibitory effects of uremic serum on DC functions.33.Hackstein H. Morelli A.E. Larregina A.T. et al.Aspirin inhibits the in vivo maturation and in vivo immunostimulatory function of murine myeloid dendritic cells.J Immunol. 2001; 165: 7053-7062Crossref Scopus (174) Google Scholar Not surprisingly, when HD patients received more efficient dialysis following the conversion to polyflux membranes, shown to produce better clearance of small-MW toxins,34.Storr M. Deppisch R. Buck R. Goehl H. The evolution of membranes for hemodialysis.in: Kas Ha. Biomedical Science and Technology. Plenum Press, New York1998: 219-233Crossref Google Scholar there was a reversal of the inhibitory effects of uremic serum on MDC, but not PDC functions. A modest improvement in clearance of urea in the HD patients followed conversion from polysulfone to polyflux membrane, but the effect on middle/large-MW molecules was not determined. Polyflux membranes have also been shown to induce less inflammatory response, potentially explaining the marginally lower serum levels of the Th1 cytokine, IL-12p70, following conversion. As middle and large MW uremic toxins also inhibit DC function, consideration of using high-flux membranes may lead to further improvement in HD patient's DC function, including a potential improvement in PDC function. Further studies to define the role of high-flux polyflux membranes on DC functions are currently underway to determine the optimal HD regime to improve DC/immune function in HD patients. In this study, we demonstrate that uremic MDC from HD patients show reduced endocytic capacity, which may in part explain the inability of uremic MDC to undergo maturation.16.Lim W.H. Kireta S. Russ G.R. Coates P.T.H. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients.Transplantation. 2006; 81: 160-168Crossref PubMed Scopus (37) Google Scholar We have prospectively shown that enhanced urea clearances using polyflux membrane have resulted in an apparent improvement in uremic MDC functions ex vivo, which may be a direct reflection of the improvement in the uremic environment (i.e. reduction in uremic toxins). Supporting this finding, uremic sera of the same HD patients maintained on polyflux membrane did not inhibit MDC functions, in contrast to sera obtained pre-membrane change. From these studies, we have demonstrated that soluble uramic toxins in HD patients inhibit both MDC and PDC functions in vitro and ex vivo. This observed functional impairment in DC may contribute to the widespread immune dysfunction reported in HD patients. Our findings indicate that improving small MW uraemic toxins clearance by using a more efficient membrane may improve MDC functions, consistent with other unpublished study, which demonstrated that enhancing HD treatment may improve immune function in CRF patients.5.Girndt M. Sester M. Sester U. et al.Molecular aspects of T- and B-cell function in uremia.Kidney Int. 2001; 78: S206-S211Crossref Google Scholar A logical next step is to confirm this initial finding by the recruitment of more patients and then to determine which dialysis modalities (e.g., daily HD, peritoneal dialysis etc) or membranes (e.g., high flux) may be superior in achieving optimal DC functions, which may be helpful in determining the best possible dialysis regimen in HD patients with known immune impairment (e.g. poor or non-respon
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