Evidence for Chronic Kidney Disease-Mineral and Bone Disorder Associated With Metabolic Pathway Changes

Abstract

Abnormalities in the levels of calcium, phosphorus, and parathyroid hormone (PTH) in serum are typical for patients with chronic kidney disease (CKD). They are used routinely to predict the onset of CKD-mineral and bone disorder (MBD). However, CKD-MBD associated with metabolic pathway imbalance is not well understood.The objective of the study was to identify endogenous metabolic signatures in patients with intact PTH using mass spectrometry-based metabolomics. This study was a cross-sectional study. Ultra performance liquid chromatography-Quadrupole Time-of-Flight/mass spectrometry-based metabolic profiling was employed to analyze serum samples from 19 disease controls (DCs) (intact parathyroid hormone [iPTH] 150–300 pg/mL) and 19 secondary hyperparathyroidism (SHPT) patients (iPTH >300 pg/mL) (the training data set) to identify metabolic biomarkers for CKD-MBD. Then, another set of samples including 19 DCs (iPTH 150–300 pg/mL) and 19 SHPT patients (iPTH >300 pg/mL) (the test data set) were used to validate the potential biomarkers identified.Metabolic profiling analyses revealed different patterns of endogenous metabolites between the SHPT and the DC groups. A total of 32 unique metabolites were identified and 30 metabolites were elevated in the iPTH compared with control serum pools. Cytidine and l-phenylalanine were downregulated in the SHPT patients. The metabolic signatures identified were assessed respectively by an internal 10-fold cross validation with an accuracy of 91.4% and an external validation with an accuracy of 71.1%, a sensitivity of 73.7%, and a specificity of 68.4%.Mass spectrometry-based metabolomic analyses for SHPT patients promises immense potential for early diagnosis and therapy monitoring. Our results indicated that the onset of CKD-MBD is associated with pathway changes of protein synthesis and metabolism, amino acid metabolism, energy metabolism, and steroid hormone metabolism, with obvious promise for better understanding the pathogenesis of this disease. Several metabolic biomarkers were identified, which warrant further development.

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

“…Individuals with secondary hyperparathyroidism (intact parathyroid hormone (PTH) 150-300 pg/ml) had lower serum concentrations of cytidine and L-phenylalanine compared to controls in a study including 76 uraemic Asian patients receiving maintenance peritoneal dialysis [105]. Different metabolic patterns were shown in the high-PTH group as compared with the low-PTH group.…”

“…Different metabolic patterns were shown in the high-PTH group as compared with the low-PTH group. Among other changes, the increased level of hydroxyproline in high-PTH patients suggested this metabolite may be a potential marker for the onset of CKD-MBD [105].…”

Plasma metabolite biomarkers related to secondary hyperparathyroidism and parathyroid hormone

“…Metabolomics is an important evolving tool of systems biology, aiming to acquire an overview of metabolic status and to identify novel potential biomarkers . Distinct metabolic variations between SHPT patients (intact parathyroid hormone [iPTH] > 300 pg/mL) and disease controls (DC) (iPTH, 150–300 pg/mL in the serum have been observed in a multivariate data analysis, however, no further screening was performed …”

“…20,21 Distinct metabolic variations between SHPT patients (intact parathyroid hormone [iPTH] > 300 pg/mL) and disease controls (DC) (iPTH, 150-300 pg/mL in the serum have been observed in a multivariate data analysis, however, no further screening was performed. 22 In this investigation, we aimed to screen out the metabolites that are significantly changed in the serum of SHPT patients compared to HC but restored or tended to be normal after parathyroidectomy. We further examined the correlation between these metabolites and PTH, as well as the diagnostic value of these metabolites.…”

“…[36][37][38][39] Besides, regional differences in D/L aspartic acid ratios were considered to be a possible indicator of the bone remodeling rate. 40 22 They mainly focused on the differential metabolites associated with CKD-mineral and bone disorder, while we mainly focused on those correlated with PTH. After comparing the differential genes, five common differential metabolites were identified, including N-acetylaspartylglutamic acid, indolepyruvate, uridine, adrenosterone and L-phenylalanine.…”