Proteomic and metabolomic approaches in the search for biomarkers in chronic kidney disease

Cañadas-Garre, Marisa; Anderson, Kerry; McGoldrick, Jayne; Maxwell, Alexander P.; McKnight, Amy Jayne

doi:10.1016/j.jprot.2018.09.020

Cited by 46 publications

(39 citation statements)

References 101 publications

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“…CKD heritability has been estimated to be high (30–75%) (Satko and Freedman, 2005; O’Seaghdha and Fox, 2011; Regele et al, 2015). CKD can be identified by well-established clinical biomarkers such as SCr levels, eGFR, albuminuria, or UACR (Cañadas-Garre et al, 2018a,b). Unfortunately, these clinical biomarkers are limited in their utility to predict individual risk of CKD or likelihood for later progression to ESRD.…”

Section: Introductionmentioning

confidence: 99%

Genetic Susceptibility to Chronic Kidney Disease – Some More Pieces for the Heritability Puzzle

et al. 2019

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Chronic kidney disease (CKD) is a major global health problem with an increasing prevalence partly driven by aging population structure. Both genomic and environmental factors contribute to this complex heterogeneous disease. CKD heritability is estimated to be high (30–75%). Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci associated with CKD, including variants in UMOD, SHROOM3 , solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and the causal pathways remain incompletely understood; other factors must be contributing to the missing heritability. Less investigated biological factors such as telomere length; mitochondrial proteins, encoded by nuclear genes or specific mitochondrial DNA (mtDNA) encoded genes; structural variants, such as copy number variants (CNVs), insertions, deletions, inversions and translocations are poorly covered and may explain some of the missing heritability. The sex chromosomes, often excluded from GWAS studies, may also help explain gender imbalances in CKD. In this review, we outline recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, sex chromosomes) that typically have received less attention than gene polymorphisms. Shorter telomere length has been associated with renal dysfunction and CKD progression, however, most publications report small numbers of subjects with conflicting findings. CNVs have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis and immunoglobulin A nephropathy. Information on mtDNA biomarkers for CKD comes primarily from case reports, therefore the data are scarce and diverse. The most consistent finding is the A3243G mutation in the MT-TL1 gene, mainly associated with focal segmental glomerulosclerosis. Only one GWAS has found associations between X-chromosome and renal function (rs12845465 and rs5987107). No loci in the Y-chromosome have reached genome-wide significance. In conclusion, despite the efforts to find the genetic basis of CKD, it remains challenging to explain all of the heritability with currently available methods and datasets. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mtDNA and sex chromosomes, hidden heritability in CKD remains elusive, and more comprehensive approaches, particularly through the integration of multiple –“omics” data, are needed.

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Section: Introductionmentioning

confidence: 99%

Genetic Susceptibility to Chronic Kidney Disease – Some More Pieces for the Heritability Puzzle

et al. 2019

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“…However, these eGFR equations are less accurate for certain individuals, such as those with low muscle mass, extreme body mass indexes, and early-stage CKD, a group whose identification is key to allow implementation of preventative measures (Gentile and Remuzzi, 2016). Extensive reviews of the literature have highlighted that there are relatively few alternative kidney function biomarkers, and none have improved upon the limitations of serum creatinine or cystatin C (Cañadas-Garre et al, 2018; Cañadas-Garre et al, 2019b). Therefore, while exclusion of chromosome Y in genomic analysis of renal disease may previously have been justifiable, it does highlight a distinct gap in our knowledge of how chromosome Y genetic variation may play a role in renal disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

The Challenges of Chromosome Y Analysis and the Implications for Chronic Kidney Disease

et al. 2019

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The role of chromosome Y in chronic kidney disease (CKD) remains unknown, as chromosome Y is typically excluded from genetic analysis in CKD. The complex, sex-specific presentation of CKD could be influenced by chromosome Y genetic variation, but there is limited published research available to confirm or reject this hypothesis. Although traditionally thought to be associated with male-specific disease, evidence linking chromosome Y genetic variation to common complex disorders highlights a potential gap in CKD research. Chromosome Y variation has been associated with cardiovascular disease, a condition closely linked to CKD and one with a very similar sexual dimorphism. Relatively few sources of genetic variation in chromosome Y have been examined in CKD. The association between chromosome Y aneuploidy and CKD has never been explored comprehensively, while analyses of microdeletions, copy number variation, and single-nucleotide polymorphisms in CKD have been largely limited to the autosomes or chromosome X. In many studies, it is unclear whether the analyses excluded chromosome Y or simply did not report negative results. Lack of imputation, poor cross-study comparability, and requirement for separate or additional analyses in comparison with autosomal chromosomes means that chromosome Y is under-investigated in the context of CKD. Limitations in genotyping arrays could be overcome through use of whole-chromosome sequencing of chromosome Y that may allow analysis of many different types of genetic variation across the chromosome to determine if chromosome Y genetic variation is associated with CKD.

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“…Quantitative analysis on discriminating metabolites revealed a statistically significant elevation of 3-hydroxybutyrate, acetate, arabinose, maltose, ribose, sucrose and tartrate with a concurrent decrease in creatinine concentration of PEW patients. There is no comparable study that utilized the metabolomics platform to elucidate the PEW mechanism in the HD population, however, prior studies have been able to identify potential early biomarkers of CKD such as trimethylamine N-oxide, kynurenine and citrulline [ 31 , 32 ], indicating abrupt amino acids metabolism in CKD.…”

Section: Discussionmentioning

confidence: 99%

Exploring Metabolic Signature of Protein Energy Wasting in Hemodialysis Patients

et al. 2020

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End-stage renal disease patients undergoing maintenance hemodialysis (HD) are vulnerable to the protein energy wasting (PEW) syndrome. Identification and diagnosis of PEW relies on clinical processes of judgment dependent on fulfilling multiple criteria drawn from serum biochemistry, weight status, predictive muscle mass, dietary energy and protein intakes. Therefore, we sought to explore the biomarkers’ signature with plasma metabolites of PEW by using 1H-nuclear magnetic resonance for an untargeted metabolomics approach in the HD population, to understand metabolic alteration of PEW. In this case-controlled study, a total of 53 patients undergoing chronic HD were identified having PEW based on established diagnostic criteria and were age- and sex-matched with non-PEW (n = 53) HD patients. Fasting predialysis plasma samples were analyzed. Partial least square discriminant analysis demonstrated a significant separation between groups for specific metabolic pattern alterations. Further quantitative analysis showed that the level of 3-hydroxybutyrate, acetate, arabinose, maltose, ribose, sucrose and tartrate were significantly increased whilst creatinine was significantly decreased (all p < 0.05) in PEW subjects. Pathway analysis indicated that PEW-related metabolites reflected perturbations in fatty acid mechanism and induction of glyoxylate and dicarboxylate pathway attributed to gluconeogenesis. These results provide preliminary data in understanding metabolic alteration of PEW and corresponding abnormal metabolites that could potentially serve as biomarkers of PEW.

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Proteomic and metabolomic approaches in the search for biomarkers in chronic kidney disease

Cited by 46 publications

References 101 publications

Genetic Susceptibility to Chronic Kidney Disease – Some More Pieces for the Heritability Puzzle

Genetic Susceptibility to Chronic Kidney Disease – Some More Pieces for the Heritability Puzzle

The Challenges of Chromosome Y Analysis and the Implications for Chronic Kidney Disease

Exploring Metabolic Signature of Protein Energy Wasting in Hemodialysis Patients

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