The effects of chronic kidney disease and renal replacement therapy on circulating dendritic cells

Dennis A. Hesselink, Michiel G. H. Betjes, Martijn A. Verkade, Petros Athanassopoulos, Carla C. Baan and Willem Weimar

Erasmus University Medical Center, Internal Medicine, Division of Nephrology and Renal Transplantation, Rotterdam, The Netherlands

Correspondence and offprint requests to: D. A. Hesselink, Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Room Ee 563 A, Erasmus MC, University Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Email: d.a.hesselink{at}erasmusmc.nl



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The mechanisms underlying the immunodeficiency of chronic kidney disease (CKD) are incompletely understood. Recently, we described decreased numbers of myeloid (m) and plasmacytoid (p) dendritic cells (DCs), considered the most important antigen-presenting cells, in peripheral blood of patients on chronic intermittent haemodialysis (CIHD). In this study, we analysed whether this reduction resulted from CKD or from renal replacement therapy (RRT).

Methods. Using flowcytometry, we quantified mDCs and pDCs in peripheral blood of patients maintained on CIHD (n = 37), continuous ambulatory peritoneal dialysis (CAPD; n = 29), and patients with CKD not receiving RRT (n = 37). Twenty-nine healthy volunteers served as controls.

Results. Patients with CKD (n = 103) had lower pDC and mDC counts compared with volunteers: 4.2 vs 8.3 and 10.0 vs 13.8x106 cells/l, respectively (P ≤ 0.001). Within the CKD group, pDC counts did not differ between patients on CIHD, CAPD and those not receiving RRT (3.6 vs 5.0 vs 4.9x106 cells/l, respectively). In the latter group, pDC numbers correlated with the glomerular filtration rate (GFR; Spearman's r = 0.49; P<0.01). In contrast, mDC counts of patients on CIHD were lower compared with patients on CAPD (7.5 vs 10.1x106 cells/l; P = 0.039) and patients not receiving RRT (13.7x106 cells/l; P<0.001). Among non-dialyzing patients, no correlation existed between GFR and mDC numbers, which were comparable to those of volunteers, even when only non-dialyzing patients with a GFR below 15 ml/min were analysed.

Conclusions. Circulating DC counts are decreased in patients with CKD; for pDCs, this reduction is primarily related to the loss of GFR, whereas the dialysis treatment appears to affect mDC numbers.

Keywords: chronic haemodialysis; chronic kidney failure; chronic renal disease; continuous ambulatory peritoneal dialysis; immunodeficiency; renal replacement therapy



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Chronic kidney disease (CKD) induces a state of immunodeficiency. Clinically, this is apparent by the high incidence of infectious complications among patients with CKD, and the excess infection-related mortality in patients on chronic intermittent haemodialysis (CIHD) as compared with the general population [1]. In addition, loss of glomerular filtration rate (GFR) is associated with a decreased vaccination response [2], an increased overall risk of cancer [3] and diminished delayed-type hypersensitivity responses [4].

The exact mechanisms responsible for the impaired immunity of CKD are incompletely understood but several immune abnormalities have been described. First, patients with CKD have low numbers of circulating T-, B- and natural killer (NK) lymphocytes [5]. Second, there is evidence that T-lymphocyte function is aberrant in dialyzing patients. Several studies have demonstrated that phenotypically, T-cells are in an activated state and display altered proliferative responses after stimulation with mitogens or soluble antigens in vitro [5,6]. However, whether CKD causes an intrinsic T-cell defect is still a matter for debate as the observed alterations in T-cell response may have resulted from a defective antigen-presenting capacity of monocytes [7].

A cell type that has hitherto received little attention in the immunodeficiency of CKD is the dendritic cell (DC). DCs are antigen-presenting cells that are able to initiate and regulate T-, B- and NK lymphocyte immunity [8]. Physiologically, DCs play a key role in the protection against pathogens, tumour surveillance and the maintenance of tolerance to self [8]. DCs originate from bone marrow progenitors and travel via blood to nonlymphoid tissues, where they reside as immature DCs that are specialized in antigen uptake. Antigen uptake in combination with an inflammatory stimulus causes immature DCs to terminally differentiate, switching these cells into an immunostimulatory mode. This maturation process is characterized by the loss of the DC ability to capture antigens and by an increased expression of distinct chemokine receptors, MHC class I and II, and diverse adhesion and costimulatory molecules on the DC surface. This enables DCs to traffic to secondary lymphoid tissue and maximally stimulate effector cells from both the innate and adaptive immune system [8].

Recently, we demonstrated that patients on CIHD have reduced numbers of DCs in their peripheral blood as compared with healthy volunteers [9]. However, it was unclear whether this was a reflection of CKD or if this resulted from CIHD treatment. In this study, we therefore compared the numbers of the two main DC subsets present in human blood, the myeloid (m) and plasmacytoid (p) DC, between a group of patients on CIHD, a group of patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and a group of patients with varying degrees of CKD not receiving renal replacement therapy (RRT). In addition, the maturation status and homing potential of these two DC subsets was studied by measuring the expression of CD83 and the chemokine receptor CCR7 on the DC surface. CD83 is a cell surface molecule that is upregulated upon antigen capture and maturation of DCs [8]. Like CD83, the expression of CCR7 increases with maturation and allows the DC to respond to the CCR7 ligands CCL19 and CCL21, enabling the cell to traffic to secondary lymphoid organs [10].



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Adult patients (>=18 years) routinely visiting our outpatient clinic, dialysis ward or admitted to the renal transplant unit to undergo kidney transplantation, were asked to participate in the study. Patients had to be on dialysis for at least 3 months and were all in a stable clinical condition. Patients with known autoimmune disease, malignancy, clinical signs of active infection or taking immunosuppressive medication were not included. Patients on RRT received treatment with recombinant erythropoetin in a dosage to maintain haemoglobin levels >=7.0 mmol/l. In addition, all patients on dialysis were treated with 1{alpha},25-dihydroxy vitamin D3. In CKD patients not receiving RRT, 1{alpha},25-dihydroxy vitamin D3 supplementation was started when the GFR fell below 30 ml/min. All patients gave informed consent. Demographic and clinical data of the patients are listed in Table 1. Healthy volunteers from our laboratory and nursing staff served as controls [11 males and 18 females; mean age±SD (range): 36±11 (22–59) years].


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Table 1. Patient characteristics

 
All patients on CIHD were dialyzed three times weekly for 4 h by use of polysulfone dialyzer membranes (F6HPS capillary dialyzers; Fresenius Medical Care AG, Bad Homburg, Germany). Water for dialysis was prepared by the use of reverse osmosis according to European guidelines [11]. The bacteriological quality of the dialysate was measured at regular intervals according to European guidelines (endotoxin levels <0.25 IU/ml and <100 colony forming units per ml). In patients with CKD not receiving RRT, the GFR was calculated using the abbreviated Modification of Diet in Renal Disease Study equation [12]:

Estimated GFR (ml/min/1.73 m2) = 186x(serum creatinine)–1.154x(age)–0.203x(0.742 if female)x(1.21 if African American).

Antibodies for staining
Fluorescence-activated cell sorter (FACS) analysis was performed using the following mouse anti-human monoclonal antibodies: fluorescein isothiocyanate (FITC)-conjugated CD34 (clone 8G12), FITC-conjugated lineage cocktail 1 [containing CD3 (SK7), CD14 (m{phi}P9), CD16 (3G8), CD19 (SJ25C1), CD20 (L27) and CD56 (NCAM16.2)], phycoerythrin (PE)-conjugated anti-IL-3 receptor {alpha} chain (CD123) (9F5), allophycocyanin-conjugated CD11c (S-HCL.3), peridinin chlorophyll protein-conjugated anti-HLA-DR (L243) (all purchased from Becton-Dickinson Biosciences, San Jose, CA, USA), PE-conjugated CD83 (HB15A17.11; DPC, Serotec, Oxford, UK), PE-conjugated anti-CCR7 (CDw197) (150503; R&D Systems Europe, Abingdon, UK), and PE-conjugated IgG2a (X39) and IgG2b (27-35) isotype control monoclonal antibodies (Becton Dickinson).

Immunofluorescence staining and flow cytometric analysis
Peripheral venous blood samples were collected in standard lithium-heparinized tubes and processed within 3 h of collection. Blood from patients undergoing CIHD was collected immediately before the start of a dialysis session. Whole blood samples were first incubated with the above-mentioned monoclonal antibodies for 30 min in the dark at room temperature. Next, erythrocytes were lysed by incubating the samples for 10 min with FACS lysing solution (Becton-Dickinson). Cells were then washed twice using FACS flow and subsequently 300.000 events were measured on a FACScalibur flow cytometer using CellQuest Pro software (Becton Dickinson). Cells that stained negative for the lineage cocktail (Lin) and positive for HLA-DR were gated and analysed for CD11c and CD123 expression. mDCs and pDCs were identified as Lin, HLA-DR+, CD11c+, CD123–/low and Lin, HLA-DR+, CD11c, CD123high, respectively. Absolute counts of mDCs and pDCs were then obtained by multiplying the proportion of each DC subset within the total leukocyte population by the absolute number of white blood cells as determined on an automated microcell counter (Sysmex F-300; TOA Medical Electronics Co. Ltd, Kobe, Japan). For the expression of CD83 and CCR7 on mDCs and pDCs, CD123PE was replaced by CD83PE or CCR7PE. The Lin, HLA-DR+, CD11c+ cells were then considered as the mDC population and within this subset the percentage of CD83- or CCR7-positive cells was determined by comparison with their respective isotype control antibodies. The same was performed for the pDC population (Lin, HLA-DR+, CD11c cells). Determination of the percentage CD83- and CCR7-positive mDCs and pDCs was performed only if a minimum of 100 events was acquired for each DC subset.

Details on the reproducibility of the flow cytometric DC assay in our laboratory were published recently [13]. In addition, the performance of lymphocyte flowcytometry in our laboratory meets the proficiency standards of the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML; http://www.skzl.nl).

Statistical analysis
All values are presented as median (range). To achieve a normal distribution, leucocyte and DC numbers, as well as the percentage CD83- and CCR7-positive mDCs and pDCs, were logarithmically transformed for statistical analysis. For comparisons between groups, the t-test, Mann–Whitney U-test, one-way ANOVA or Kruskal–Wallis test were used, as appropriate. Post hoc analysis was performed using Bonferroni's test for multiple comparisons or Mann–Whitney U-test. P-values at {alpha}<0.05 were considered statistically significant. For correlation analysis, Spearman's rank correlation coefficient (rs) was calculated.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Total leucocyte counts were not different between volunteers and the group of patients with CKD: median (range): 6.1 (3.8–9.7) vs 6.6 (2.9–13.7)x 109 cells/l. Within the CKD group, there existed a difference in total leucocyte numbers (P<0.01; Table 2). This overall difference was caused by the higher leucocyte count of CKD patients not receiving RRT compared with patients on CIHD (P = 0.011; Table 2). Leucocyte numbers of CAPD patients were comparable with those of patients on CIHD and patients not on dialysis.


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Table 2. Haematologic parameters of the study groups

 
Numbers of circulating DCs are decreased in patients with CKD
Total DC numbers of CKD patients were lower compared with the volunteer group: 16.1 (4.0–41.4) vs 20.6 (11.1–43.1)x106 cells/l (P<0.001). Within the CKD group, patients on CIHD had the lowest DC counts, which were significantly different from DC numbers in patients not on dialysis (P = 0.001) but not from patients on CAPD (Table 2). Total DC numbers of patients on CIHD, CAPD and those not on dialysis were all lower compared with volunteers (P<0.05). The difference in total DC numbers between volunteers and patients with CKD resulted from a difference in both the myeloid and the plasmacytoid DC subset: 13.8 vs 10.0x106 cells/l (P<0.01) and 8.3 vs 4.2x106 cells/l (P<0.001), respectively. mDC counts were lower in CIHD patients compared with patients not receiving RRT (P<0.001) and patients on CAPD (P = 0.039; Table 2). Compared with volunteers, only dialyzing patients had significantly reduced mDC counts. Plasmacytoid DC counts were comparable within the CKD group, although they were numerically lowest in CIHD patients (Table 2).

Loss of GFR is related to decreased numbers of plasmacytoid but not myeloid DCs
Next, we investigated the relationship between the severity of CKD and DC numbers more closely. As depicted in Figure 1A, there existed an inverse relationship between serum creatinine and pDC counts (rs = –0.45, P<0.01). No such correlation was observed between mDC numbers and serum creatinine (rs = –0.06). A similar relationship between (the loss of) renal function and circulating pDC counts was observed when numbers of this cell type were correlated with the estimated GFR (Figure 1B; rs = 0.49; P<0.01). In contrast, there existed no significant correlation between mDC counts and GFR (rs = 0.15). When GFR was classified according to the National Kidney Foundation classification of CKD [12], a trend towards lower pDC counts with advancing stages of CKD was observed (overall P = 0.007; Figure 1C).



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Fig. 1. The correlation between individual plasmacytoid dendritic cell (pDC) counts and serum creatinine (A), between individual pDC counts and estimated GFR (B), and between individual pDC counts and class of CKD (C).

 
The number of patients with hypertensive nephropathy or diabetes mellitus was randomly divided between the different classes of CKD. Among patients with CKD not receiving RRT, there was no difference in mDC counts between patients with or without a certain form of co-morbidity (hypertensive or diabetic nephropathy, polycystic kidney disease or glomerulonephritis; data not shown). However, patients with diabetes mellitus had significantly lower pDC counts compared with patients without this disease: 3.8 (1.2–5.8) vs 5.4 (0.5–17.9); P = 0.03. Nevertheless, the correlation between GFR and pDC numbers in non-dialyzing CKD patients remained significant when the eight patients with diabetes were excluded from the analysis (rs = 0.54; P = 0.002). Other forms of co-morbidity did not affect pDC numbers (data not shown).

CIHD but not CAPD, is related to decreased numbers of mDCs
To assess a potential (additional) effect of dialysis treatment, we compared DC counts of patients treated with CIHD or CAPD with non-dialyzing patients who only had a GFR below 15 ml/min (CKD class 5). Plasmacytoid DC counts were again not different between the CKD class 5 [3.2 (0.5–11.5)x106 cells/l] and the CAPD and CIHD groups (Table 2). In contrast, mDC numbers of non-dialyzing patients with CKD class 5 (10.9x106 cells/l) were comparable to healthy volunteers but significantly higher when compared with patients on CIHD (P = 0.04; Figure 2). Finally, no effect of residual diuresis on circulating DC numbers was observed within the CIHD and CAPD groups (data not shown).



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Fig. 2. Absolute counts of myeloid DCs in peripheral blood of patients with CKD class 5 (GFR <15 ml/min) not receiving RRT, on CIHD or on CAPD. Bars represent median values; P-values indicate the difference between patients on CIHD and patients with CKD class 5 or between patients on CIHD and patients on CAPD.

 
CKD does not influence expression of DC activation markers
No evidence was found for DC activation in peripheral blood as demonstrated by the low percentage of CD83+ and CCR7+ mDCs, and CD83+ pDCs (Table 2). In agreement with the literature [10], the majority of pDCs expressed CCR7 at a low level (‘dim’) but high CCR7 expression was never observed. When CD83 and CCR7 expression was compared between groups, only the percentage CCR7+ mDCs was found to differ between volunteers and CKD patients: 9.86 (1.84–14.60) vs 6.52 (1.04–23.33), respectively; P<0.001. Compared with patients on CAPD, non-dialyzing patients had a lower percentage CCR7+ mDCs (Table 2) but the absolute counts of CCR7+ mDCs were not different between these two groups (0.9 vs 0.7x106 cells/l, respectively).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In this study, we demonstrate that CKD and dialysis treatment are associated with decreased numbers of DCs in peripheral blood. Terminally differentiated DCs are potent antigen-presenting cells, while immature pDCs are a major source of interferon-{alpha}, which is important for viral defence [8]. Under steady-state conditions, circulating DCs are thought to extravasate continuously into tissue and lymph nodes where they maintain the peripheral DC pool. In addition, these cells may selectively home to sites of tissue damage during inflammation [8]. Our observations may therefore form yet another explanation for the high incidence of bacterial infections among patients with CKD that has previously been attributed to decreased lymphocyte counts, alterations in T-cell and monocyte function, and various abnormalities of the innate immune system [5–7]. Moreover, the reduction of pDCs in peripheral blood could also explain the disturbed immunity against viruses that appears to exist in patients with CKD [2,14].

In patients treated with CIHD or CAPD, both the plasmacytoid and the myeloid DC subset were affected, whereas in CKD patients not receiving RRT, only pDC numbers were significantly reduced compared with controls. The finding of a negative correlation between pDC counts and renal function among non-dialyzing patients indicates that the decreased number of circulating pDCs in patients with CKD principally results from the loss of GFR. However, the observation that non-dialyzing patients with diabetic nephropathy had lower pDC counts compared with patients suffering from other causes of renal insufficiency suggests that co-morbidity may also influence peripheral blood pDC counts. Importantly, the reduction of pDC counts among non-dialyzing patients was already apparent at a relatively mild degree of CKD. These observations are in line with the findings of DaRoza et al. [2] who observed a correlation between (the loss of) GFR and HBV vaccination response. In that study, patients with the worst kidney function were less likely to seroconvert after HBV vaccination compared with patients with moderate renal insufficiency [2]. Interestingly, mDC numbers were only significantly reduced in patients maintained on dialysis. Among non-dialyzing patients, no correlation was observed between mDC counts and renal function. In addition, residual diuresis of patients treated with either CIHD or CAPD did not affect mDC numbers. This suggests that, in contrast to the pDC subset, the reduction of mDC numbers in peripheral blood of patients with CKD results from dialysis treatment rather than the loss of GFR.

Our findings are in agreement with the results of several studies that investigated DCs in the skin of patients with CKD [15–17]. Two types of cutaneous DCs can be distinguished: the Langerhans cell (LC) and the dermal DC, both of which are thought to differentiate from mDCs. The number of LCs in the skin of patients on CIHD and CAPD was found to be significantly lower compared with healthy volunteers, whereas LC counts were not different between non-dialyzing patients and control subjects [16]. In contrast, McKerrow et al. [15] did observe a reduction in epidermal LCs in patients with CKD not receiving RRT. With regard to dermal DCs, the results are less consistent: compared with healthy controls, dermal DC numbers were reduced in patients on CAPD, comparable in patients on CIHD and elevated in patients with CKD not on dialysis [17].

At present, the mechanism underlying the CKD-associated reduction in circulating DCs is unclear but it may involve an impaired generation of DCs from bone marrow progenitors. Indirect evidence for this possibility comes from the study by Ando et al. [18] who demonstrated that thrombocytopaenia is a common finding among patients on RRT. The principal cause for the decreased number of circulating platelets was a reduced megakaryocyte production in the bone marrow, possibly as a result of the presence of undialyzable marrow-suppressive toxins [18]. A second explanation for the low numbers of circulating DCs could be an increased peripheral DC turnover. Although no data on the lifespan of human DCs exist, several investigators have demonstrated that monocytes and lymphocytes from patients with CKD are more susceptible to undergo apoptosis in comparison with healthy volunteers [5,19]. Consistent with our observations on DCs, the rate of mononuclear cell apoptosis was higher in patients undergoing CIHD compared with non-dialyzing patients [19]. A third explanation could be a redistribution of DCs to peripheral tissue. Although the skin does not appear to be the site of such a redistribution [15–17], increased DC migration to other peripheral tissues or secondary lymphoid organs remains a theoretical possibility.

The percentage of DCs expressing CD83 or CCR7 was not altered in patients with CKD, suggesting that under uraemic conditions, DCs do not undergo (increased) maturation in the circulation. However, under physiologic conditions, maturation of DCs only occurs after antigen uptake in combination with an appropriate inflammatory signal, and therefore this process is initiated in peripheral tissue and completed in the afferent lymphatics and secondary lymphoid organs [8]. A limitation of the present study is the lack of functional DC assays. Future work should address the effects of CKD and its treatment on DC function. However, as the number of circulating DCs in patients with CKD is low, isolation of adequate cell numbers to perform such assays will not be easy. Furthermore, the precise effect of dialysis treatment on circulating mDCs requires further investigation.

In conclusion, we show that in patients with CKD, DC counts are markedly reduced compared with healthy volunteers. The quantitative changes in circulating pDCs result mainly from the loss of GFR, whereas the reduction in mDC numbers appears to relate to the dialysis treatment itself. Our findings may provide an additional explanation for the immunodeficiency of CKD.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 26. 1.05
Accepted in revised form: 15. 4.05





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