Reduced Capacity of Mononuclear Cells to Synthesize Cytokines against an Inflammatory Stimulus in Uremic Patients

Abstract

Background: The local production of cytokines and phagocytosis is pivotal in innate immunity. Uremic patients have a high infectious morbidity, but it remains unclear if this arises from incompetence of these local cellular functions. Methods: In 30 predialysis uremic patients and 20 controls, we studied the intracellular cytokine synthesis by mononuclear cells in response to stimulation. Moreover, phagocytic activity by leukocytes was tested. Lipopolysaccharide- or mitogen-stimulated peripheral blood cells were labeled with anti-CD14 and -CD4 antibodies, respectively and subjected to intracellular cytokine staining and flow cytometry. Tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8 synthesis was examined in CD14⁺ monocytes. IFN-γ and IL-4 synthesis was examined in CD4⁺ helper T cells to determine their Th1 or Th2 phenotype. The flow cytometric analysis of phagocytosis of opsonized bacteria was performed in whole blood. Results: Uremic patients exhibited a significantly reduced monokine response and inhibited development of helper T cells into Th1 or Th2 phenotypes compared with control subjects. Their phagocytic activity was comparable to control subjects. No clinical parameters were linked to in vitro cytokine production and phagocytic activity. Conclusions: Mononuclear cells in uremic patients are hyporeactive to inflammatory challenge and this may be one reason why uremic patients are vulnerable to infections.

Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases

“…Clinical manifestations of these alterations result both from the higher concentrations of β 2 M (e.g., DRA) as well as the altered MHC/non-classical MHC function, i.e., the phenotype of β 2 M deficiency highlighted in the β 2 M knockout mice. Observations in these animals parallel the clinical observations and laboratory associations in patients with renal dysfunction: dysregulated IFN-γ production (312, 313), tuberculosis (314–316), acute infections, and suboptimal antibody responses [all reviewed in Ref. (317)].…”

Effect of Hydrogen Sulfide on Essential Functions of Polymorphonuclear Leukocytes

“…It has been shown that PMNLs from healthy subjects react differently to uremic toxins than PMNLs from CKD patients [ 108 , 109 ]. Mononuclear cells from CKD patients have a significantly decreased cytokine production when exposed to lipopolysaccharide [ 110 ] and a diminished proliferative response to antigens in vitro [ 111 ]. One limitation of this study is that we only determined the concentration of releasing substances based on the literature and did not measure the amount of H 2 S generated during experiments.…”

Uremic toxins are conditional danger- or homeostasis-associated molecular patterns

“…However, the issue of whether host innate immune system uses classical DAMP receptors to sense the elevation of all of other water-soluble and protein-bound UTs remains unknown. It is biochemically difficult for a few classical DAMP receptors, such as TLRs and NLRs, to bind with high affinity to all of those UTs and initiate inflammation efficiently, considering that reduced expression of TLR4 is found in uremic patients (58). …”