A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients

Abstract

BackgroundChronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunity) coexist. In this setting, circulating uremic toxins and microinflammation play a critical role. This condition, already present in the last stages of renal damage, seems to be enhanced by the contact of blood with bioincompatible extracorporeal hemodialysis (HD) devices. However, although largely described, the cellular machinery associated to the CKD- and HD-related immune-dysfunction is still poorly defined. Understanding the mechanisms behind this important complication may generate a perspective for improving patients outcome.MethodsTo better recognize the biological bases of the CKD-related immune dysfunction and to identify differences between CKD patients in conservative (CKD) from those in HD treatment, we used an high-throughput strategy (microarray) combined with classical bio-molecular approaches.ResultsImmune transcriptomic screening of peripheral blood mononuclear cells (1030 gene probe sets selected by Gene-Ontology) showed that 275 gene probe sets (corresponding to 213 genes) discriminated 9 CKD patients stage III-IV (mean ± SD of eGFR: 32.27±14.7 ml/min) from 17 HD patients (p < 0.0001, FDR = 5%). Seventy-one genes were up- and 142 down-regulated in HD patients. Functional analysis revealed, then, close biological links among the selected genes with a pivotal role of PTX3, IL-15 (up-regulated in HD) and HLA-G (down-regulated in HD). ELISA, performed on an independent testing-group [11 CKD stage III-IV (mean ± SD of eGFR: 30.26±14.89 ml/min) and 13 HD] confirmed that HLA-G, a protein with inhibition effects on several immunological cell lines including natural killers (NK), was down-expressed in HD (p = 0.04). Additionally, in the testing-group, protein levels of CX3CR1, an highly selective chemokine receptor and surface marker for cytotoxic effector lymphocytes, resulted higher expressed in HD compared to CKD (p < 0.01).ConclusionTaken together our results show, for the first time, that HD patients present a different immune-pattern compared to the un-dialyzed CKD patients. Among the selected genes, some of them encode for important biological elements involved in proliferation/activation of cytotoxic effector lymphocytes and in the immune-inflammatory cellular machinery. Additionally, this study reveals new potential diagnostic bio-markers and therapeutic targets.

Lymphocyte depletion and subset alteration correlate to renal function in chronic kidney disease patients

“…51 However, other researches indicated that longtime dialysis enhances NK cytotoxic activity, 16,52 which was confirmed by immune transcriptomic screening of peripheral blood mononuclear cells of dialysis patients. 53 In this study, we found a negative correlation between eGFR and NK cell percentage which could not be entirely attributed to the decrease of other cell compartments. Univariate analysis showed that NK cell proportion was positively associated with older age, history of hypertension and CVD and biochemical indexes related to uremia status including serum albumin, BUN, Cr, cystatin C, ferritin and b2-M and negatively associated with diastolic blood pressure, bicarbonate, hemoglobin and lipid.…”

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

“…21 Cross-sectional studies of patients with CKD have shown that lower mitochondrial function, indicated by metabolites from urine and gene expression from peripheral blood, correlated with more severe CKD. 22,23 In this study, the association between mtDNA copy number and incident CKD was slightly attenuated after controlling for WBC count, a marker of systematic inflammation, but remained independent of WBC count and hsCRP. These results suggest mtDNA copy number may represent the effect of cumulative exposure to oxidative stress that is not captured in the one-time measures of WBC count and hsCRP.…”

The Influence of Hemodialysis on T Regulatory Cells: A Meta-Analysis and Systematic Review

“…(2) All types of articles except reviews. (3) Studies that performed FACS analysis with the following antibodies: (1) CD4+, (2) CD25 bright (instead of just CD25+), (3) CD127-and/or (4) FoxP3+. If only CD25+ was used instead of CD25 bright then this must have been combined with either CD127 negativity or FoxP3 positivity for inclusion in our study.…”

“…Different research groups have demonstrated that patients with chronic kidney disease (CKD) stages G5 not on dialysis (CKD G5), CKD GFR stages G5 on dialysis patients (CKD G5D) or patients with acute kidney injury [2] suffer from immune system dysregulation characterized by immune incompetence as well as signs of chronic inflammation [3] . The condition of uremia per se is characterized by a series of metabolic disturbances that produce an imbalance between immunostimulation and immunosuppression [4] .…”