title: A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients.
abstract: BACKGROUND
  Chronic 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Immune 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).
  
  
  CONCLUSIONS
  Taken 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.
authors.affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A, Stefani 1, Verona 37126, Italy. gianluigi.zaza@univr.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.forename: Simona
authors.initials: S
authors.lastname: Granata
authors.forename: Federica
authors.initials: F
authors.lastname: Rascio
authors.forename: Paola
authors.initials: P
authors.lastname: Pontrelli
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Dell'Oglio
authors.forename: Sharon Natasha
authors.initials: SN
authors.lastname: Cox
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pertosa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D016002:Discriminant Analysis; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D059951:HLA-G Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000378:metabolism; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015854:Up-Regulation; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D000073883:CX3C Chemokine Receptor 1; D059951:HLA-G Antigens; D019409:Interleukin-15; D019707:Receptors, Chemokine; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C095235:CX3CR1 protein, human