Impact of Different Immunosuppressive Regimens on Antigen-Presenting Blood Cells in Kidney Transplant Patients

Atherosclerotic cardiovascular disease is a major cause of death in renal transplant (TX) recipients. Atherosclerotic lesions are characterized by monocytic infiltration. Circulating monocytes can be divided into functionally distinct subpopulations, among which CD14++CD16+ and CD14+CD16+ monocytes (summarized as CD16+ monocytes) are proinflammatory cells. We hypothesized that the frequency of circulating CD16+ monocytes is associated with subclinical atherosclerosis in TX patients. Monocyte subpopulations were quantified in 95 TX and 31 hemodialysis patients (HD). In TX patients, subclinical atherosclerosis was determined by carotid intima media thickness (IMT) measurement. TX patients had lower frequencies of CD16+ monocytes than HD patients. When stratifying by immunosuppressive treatment, patients on methylprednisolone (MP) therapy had fewer CD14+CD16+ monocytes than patients not receiving MP. CD14+CD16+ monocytes decrease very shortly after transplantation. CD14+CD16+ monocyte frequency correlated with IMT in TX recipients (r = 0.34, p < 0.001). This correlation was most pronounced among patients without MP treatment (r = 0.55, p = 0.02). In a multivariate regression analysis, the association of CD14+CD16+ monocytes with IMT was independent from traditional cardiovascular risk factors. The frequency of proinflammatory CD14+CD16+ monocytes is independently associated with subclinical atherosclerosis in transplant recipients. Further studies on the association between circulating leukocytes and atherosclerosis should take monocyte heterogeneity into account.

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“…Recent preliminary data showed a partial reduction in CD16+ monocyte count in a group of TX recipients (25). Our report confirms these data.…”

Section: Discussionsupporting

confidence: 91%

“…Similarly, patients suffering from end-stage renal disease have higher numbers of proinflammatory CD14+CD16+ monocytes compared to healthy controls (8)(9)(10)(11)(12). This shift in monocyte subpopulations may contribute to the accelerated atherosclerosis in dialysis patients.…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory CD14+CD16+ Monocytes Are Associated With Subclinical Atherosclerosis in Renal Transplant Patients

Ulrich

Heine

Gerhart

et al. 2008

American Journal of Transplantation

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“…In line with our results, the presence of an increased percentage of intermediate and non-classical monocytes in end-stage kidney disease patients undergoing dialysis has been reported [25], [26], [28], [32], [33] Scherberich et al found an increase in the monocyte subset co-expressing CD14 with CD16 in patients with chronic renal failure [27]. The authors investigated the effect of different immunosuppressive regimens on the frequency of intermediate and non-classical monocytes.…”

Section: Discussionsupporting

confidence: 90%

A Shift towards Pro-Inflammatory CD16+ Monocyte Subsets with Preserved Cytokine Production Potential after Kidney Transplantation

et al. 2013

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BackgroundThe presence of monocyte-macrophage lineage cells in rejecting kidney transplants is associated with worse graft outcome. At present, it is still unclear how the monocyte-macrophage related responses develop after transplantation. Here, we studied the dynamics, phenotypic and functional characteristics of circulating monocytes during the first 6 months after transplantation and aimed to establish the differences between kidney transplant recipients and healthy individuals.MethodsPhenotype, activation status and cytokine production capacity of classical (CD14++CD16−), intermediate (CD14++CD16+) and non-classical (CD14+CD16++), monocytes were determined by flow cytometry in a cohort of 33 healthy individuals, 30 renal transplant recipients at transplantation, 19 recipients at 3 months and 16 recipients at 6 months after transplantation using a cross-sectional approach.ResultsThe percentage of both CD16+ monocyte subsets was significantly increased in transplant recipients compared to healthy individuals, indicative of triggered innate immunity (p≤0.039). Enhanced production capacity of tumor necrosis factor-α, interferon-γ and interleukin-1β was observed by monocytes at transplantation compared to healthy individuals. Remarkably, three months post-transplant, in presence of potent immunosuppressive drugs and despite improved kidney function, interferon-γ, tumor necrosis factor-α and interleukin-10 production capacity still remained significantly increased.ConclusionOur data demonstrate a skewed balance towards pro-inflammatory CD16+ monocytes that is present at the time of transplantation and retained for at least 6 months after transplantation. This shift could be one of the important drivers of early post-transplant cellular immunity.

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“…We did not evaluate the clinical significance of this reduced HLA-DR expression but, this might be one of the reasons why organ transplant recipients are 'immunocompromised', transforming an otherwise simple viral infection into a dangerous, severe complication. Similarly, Scherberich et al [11] also found a downregulation in monocyte surface antigen CD14 (lipopolysaccharide receptor) and CD16 (Fc-III receptor) by flow cytometry in transplant recipients.…”

Section: Discussionmentioning

confidence: 77%

Oxidative Stress and ‘Monocyte Reprogramming’ after Kidney Transplant: A Longitudinal Study

Cal¹,

Silva²,

Cruz³

et al. 2008

Blood Purif

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Uremia has been implicated in increased oxidative stress (OS) and decreased monocyte HLA-DR expression in chronic kidney disease (CKD) patients. Thus, one would expect normalization of these parameters after successful kidney transplant (KTx). Our aim was to describe patterns of OS and HLA-DR expression after KTx and to explore the effect of renal function and different immunosuppression regimens. 30 KTx patients (20 male; 48 ± 11 years) were enrolled and compared with 20 healthy controls. We measured advanced oxidation protein products (AOPP) and the percentage of monocytes expressing HLA-DR (%DR+) before (preKTx) and after KTx (on days 2, 30, 90, 180 and after 1 year). Compared to controls, patients had a higher preKTx AOPP (152.6 vs. 69.3 µmol/l; p < 0.001). AOPP decreased at 48 h after KTx, achieving values similar to controls. Thereafter, it increased again and remained significantly higher compared to controls, returning to preKTx levels at 90 days. Prior to KTx there was a trend for lower %DR+ in KTx patients compared to controls (96 vs. 98%; NS). Following KTx, patients had a lower %DR+ in the 1st month; then it gradually returned to preKTx levels during the 1st year; at no time did it reach a value similar to controls. Cyclosporine (CyA)-treated patients had a significantly higher AOPP (161.5 vs. 99.5 µmol/l; p = 0.03) and a lower %DR+ (91.7 vs. 96.4; p < 0.05) at 30 days than patients on tacrolimus (FK). Patients on mycophenolate mofetil (MMF) showed a low AOPP (106.9 vs. 168.1 µmol/l; p = 0.05) and a high %DR+ (96.7 vs. 88.2%; p = 0.001) than those on everolimus. After 3 months, CyA-treated patients had a non-significant increase in AOPP levels, whereas those on FK showed a decrease (p < 0.05) as did those treated with MMF (p < 0.05). Successful KTx reduced but did not normalize AOPP, suggesting ongoing OS, perhaps due to persistent mild renal dysfunction and the effects of immunosuppression. HLA-DR expression remained low after KTx, which may be a possible contributing factor to infectious complications after transplantation. Immunosuppressive agents appear to have diverse effects on OS and HLA-DR expression.

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Impact of Different Immunosuppressive Regimens on Antigen-Presenting Blood Cells in Kidney Transplant Patients

Cited by 16 publications

References 11 publications

Proinflammatory CD14+CD16+ Monocytes Are Associated With Subclinical Atherosclerosis in Renal Transplant Patients

Proinflammatory CD14+CD16+ Monocytes Are Associated With Subclinical Atherosclerosis in Renal Transplant Patients

A Shift towards Pro-Inflammatory CD16+ Monocyte Subsets with Preserved Cytokine Production Potential after Kidney Transplantation

Oxidative Stress and ‘Monocyte Reprogramming’ after Kidney Transplant: A Longitudinal Study

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