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Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease.

ABSTRACT: Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts consisting of age-matched individuals with and without CKD. Sera were evaluated for antigen-specific IgG titres and the functionality of antibody to SEn was assessed in a serum bactericidal assay. Surprisingly, patients with CKD and control subjects had comparable levels of IgG against TT and DT, suggesting preserved humoral memory responses to antigens encountered early in life. Lipopolysaccharide-specific IgG titres and serum bactericidal activity in patients with CKD were also not inferior to controls. CMV-specific IgG titres in seropositive CKD patients were similar or even increased compared to controls. Therefore, whilst responses to new vaccines in CKD are typically lower than expected, antibody responses to antigens commonly encountered prior to CKD onset are not. The immunodeficiency of CKD is likely characterised by failure to respond to new antigenic challenges and efforts to improve patient outcomes should be focussed here.

SUBMITTER: Wall NA

PROVIDER: S-EPMC5901993 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease.

Wall Nadezhda A NA Dominguez-Medina C Coral CC Faustini Sian E SE Cook Charlotte N CN McClean Andrew A Jesky Mark D MD Perez-Toledo Marisol M Morgan Matthew D MD Richter Alexandra G AG Ferro Charles J CJ Cockwell Paul P Moss Paul A PA Henderson Ian R IR Harper Lorraine L Cunningham Adam F AF

PloS one 20180416 4

Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts co ...[more]

PMID: 29659606

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Project description:Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

Project description:Several reports have focused on the identification of biological elements involved in the development of abnormal systemic biochemical alterations in chronic kidney disease, but this abundant literature results most of the time fragmented. To better define the cellular machinery associated to this condition, we employed an innovative high-throughput approach based on a whole transcriptomic analysis and classical biomolecular methodologies. The genomic screening of peripheral blood mononuclear cells revealed that 44 genes were up-regulated in both chronic kidney disease patients in conservative treatment (CKD, n=9) and hemodialysis (HD, n=17) compared to healthy subjects (NORM) (p<0.001, FDR=1%). Functional analysis demonstrated that 11/44 genes were involved in the oxidative phosphorylation system (OXPHOS). Western blotting for COXI and COXIV, key constituents of the complex IV of OXPHOS, performed on an independent testing-group (12 NORM, 10 CKD and 14 HD) confirmed the elevated synthesis of these subunits in CKD/HD patients. However, complex IV activity was significantly reduced in CKD/HD patients compared to NORM (p<0.01). Finally, CKD/HD patients presented higher reactive oxygen species and 8-hydroxydeoxyguanosine levels compared to NORM. Taken together these results suggest, for the first time, that CKD/HD patients may have an impaired mitochondrial respiratory system and this condition may be both the consequence and the cause of an enhanced oxidative stress. Experiment Overall Design: For microarray analysis, we studied subjects included in the training group. This population included 8 healthy subjects (NORM), 9 patients with Chronic kidney disease (CKD) on stage II-III (CKD II-III) (mean±SD of estimated GFR by MDRD formula: 41.4±4.3 ml/min) and 17 patients undergoing hemodialysis treatment (HD).All HD patients were stably treated, for at least 1 year, three times a week (4-5 hours per session), using synthetic membrane dialyzers. During the study period, no CKD patients received dialysis treatment. In addition, all patients suffering from infectious diseases, diabetes, chronic lung diseases, neoplasm, or inflammatory diseases and patients receiving antibiotics, corticosteroids, or nonsteroidal anti-inflammatory agents were excluded. No patients had symptomatic coronary artery diseases or a family history of premature cardiovascular diseases. For all subjects, 20 ml of whole blood were collected. For HD patient the biological material was obtained at the beginning of the second HD session of the week. PBMC were isolated by density separation over a Ficoll-PaqueTM (GE healthcare, Sweden) gradient (460g for 30 min). Cells were then counted and their viability was assessed by trypan blue exclusion (>90% PBMC were viable). Total RNA was isolated by RNeasy mini kit Qiagen (QIAGEN AG, Basel, Switzerland) from a minimum of 5 milion cryopreserved PBMC. RNA was, then, processed and hybridized to the GeneChip Human Genome Plus 2.0 or U133A oligonucleotide microarray (Affymetrix, Santa Clara, CA, USA)

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Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease.

Publications

Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease.

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