Monocyte implication in renal allograft dysfunction

Abstract

SummaryMacrophages are involved in the development and progression of kidney fibrosis. The aim of this study was to analyse the phenotype of circulating monocytes and their ability to predict kidney allograft dysfunction in living kidney transplant recipients. Whole blood samples from 25 kidney recipients and 17 donors were collected at five time-points. Monocyte phenotype was analysed by flow cytometry, and interleukin (IL)-10 and soluble CD163 by enzyme-linked immunosorbent assay. One week after transplantation, surface CD163 and IL-10 levels increased significantly from baseline [2·99 ± 1·38 mean fluorescence intensity (MFI) to 5·18 ± 2·42 MFI for CD163; 4·5 ± 1·46 pg/ml to 6·7 ± 2·5 pg/ml for IL-10]. This CD163 increase correlated with 4-month creatinine levels (r = 0·4394, P = 0·04). However, soluble CD163 decreased significantly from baseline at 1 week (797·11 ± 340·45 ng/ml to 576·50 ± 293·60 ng/ml). CD14 + CD16 -monocytes increased at 4 months and correlated positively with creatinine levels at 12 and 24 months (r = 0·6348, P = 0·002 and r = 0·467, P = 0·028, respectively) and negatively with Modification of Diet in Renal Disease (MDRD) at 12 months (r = 0·6056, P = 0·003). At 4 months, IL-10 decreased significantly (P = 0·008) and correlated positively with creatinine at 2 years (r = 0·68, P = 0·010) and with CD14 + CD16 -monocytes at 4 months (r = 0·732, P = 0·004). At 24 h, levels of human leucocyte antigen D-related declined from 12·12 ± 5·99 to 5·21 ± 3·84 and CD86 expression decreased from 2·76 ± 1·08 to 1·87 ± 0·95. Both markers recovered progressively until 12 months, when they decreased again. These results indicate that monitoring monocytes could be a promising new prognostic tool of graft dysfunction in renal transplant patients.

Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury

“…21 Increasing evidence shows that intragraft macrophages, particularly activated macrophages, correlate with a poor outcome in renal transplantation in humans and animal models. [22][23][24][25][26][27][28][29] In addition, a-SMA + myofibroblast accumulation has been recognized as an early marker of chronic renal allograft dysfunction. 30,31 Of note, CD68 + macrophages and a-SMA + myofibroblasts colocalize in areas of active interstitial fibrosis in renal allografts.…”

“…30,31 Of note, CD68 + macrophages and a-SMA + myofibroblasts colocalize in areas of active interstitial fibrosis in renal allografts. 25,27,29 Although macrophages may stimulate renal fibrosis in an indirect fashion by producing proinflammatory and profibrotic cytokines and growth factors, 13 a direct link between inflammatory macrophages and myofibroblast accumulation during chronic allograft rejection has remained undefined. In this study, we confirmed that intragraft CD68 + macrophages correlated with loss of allograft function and the development of interstitial fibrosis in patients with chronic active allograft rejection, consistent with previous observations.…”

“…In this study, we confirmed that intragraft CD68 + macrophages correlated with loss of allograft function and the development of interstitial fibrosis in patients with chronic active allograft rejection, consistent with previous observations. [23][24][25][26][27][28][29] The new finding in this study was the identification that macrophages can transform into collagen-producing myofibroblasts, providing a novel mechanism for the direct involvement of macrophages in interstitial fibrosis during chronic renal allograft rejection. This MMT process was delineated by fate-mapping in combination with confocal microscopy and flow cytometry which demonstrated that 37% of the total a-SMA + myofibroblast population in the renal allograft was derived from recipient bone marrow myeloid cells.…”

Early Macrophage Infiltration and Sustained Inflammation in Kidneys From Deceased Donors Are Associated With Long-Term Renal Function

“…Our group showed that circulating monocytes could be useful as a prognostic tool with respect to graft dysfunction in living kidney recipients . In this work, we focus on gene expression of inflammatory and fibrotic markers and macrophage infiltration in kidneys from DDs and LDs at the time of transplantation and after 4 months.…”

Interpreting CD56+ and CD163+ Infiltrates in Early versus Late Renal Transplant Biopsies

“…Previous studies in solid organ transplantation suggest that NK cells are paradoxically involved in both graft acceptance and dysfunction, through their influence on the immune pathways of allograft tolerance and rejection, respectively [8][9][10] . Meanwhile, it is suggested that it could be useful to analyze CD163 by flow cytometry and enzyme-linked immunosorbent assay in the prediction of renal graft function after transplantation [11] . However, little is known about the exact mechanisms by which CD56+ or CD163+ cells contribute to the rejection or acceptance of kidney allografts.…”