The 'Omics' Techniques Help Depicting the Future of Precision Medicine in Chronic Kidney Disease-Mineral and Bone Disorders
The evolving therapies to treat the complications and replace kidney, although having prolonged the life span of patients with chronic kidney disease (CKD), still leave critical issues (e.g. cardiovascular risks). The ‘omics’ techniques (e.g. genomics, proteomics, metabolomics, and transcriptomics) are “molecular glasses” which lead us to the full bloom of precision medicine.
Challenges in CKD-MBD
Chronic kidney disease (CKD) is caused by a range of pathogenesis and becoming the leading burden of mortality and morbidity in the world. It is assumed that CKD will become the 5th most common cause of death worldwide in 2040.?Despite the big leaps made in the last decades, we are still facing a lot of unmet needs. For instance, we still do not have specialized target lab values among different age, gender, and race. In addition, no approved or well-tested treatment has been discovered to retard the progress of vascular calcification and promote the survival rate. On the basis of renal replacement techniques development, how to balance the life quality and the excessive intake of minerals is still a huge problem. Furthermore, we need to know how to deal with aging, inflammation, and nutrition deficiency to improve the outcomes of CKD patients.
Among all these problems, chronic kidney disease-mineral and bone disorders (CKD-MBD) has long been discussed but difficult to address. Cardiovascular events due to vascular calcification and fracture due to osteoporosis are two main reasons that lead to low quality of life and death.
Precision medicine is a broad and obscure concept which came following the rise of gene engineering. Different from personalized medicine, precision medicine put more emphasis on identification of clinical patterns using advanced technologies. Such diagnostic strategies and targeted treatments requires a deep understanding of disease biology and the ability to dissect the relationship between molecular and genetic factors and their phenotypic consequences. As the “omics” techniques keep developing, we are gaining new tools that are powerful to help us understand more essential pathogenesis and seek more precise therapies of CKD-MBD.
Metabolomics
Methods for metabolomics mainly include nuclear magnetic resonance (NMR), mass spectrometry (MS), and metabolic flux analysis (MFA). These methods can be adopted alone or in combination to the others to identify and quantify a wide range of metabolites. MS can be coupled with other analytical techniques and further classified into ion mobility-MS (IM-MS), direct injection-MS (DI-MS), liquid chromatography-MS (LC–MS), capillary electrophoresis-MS (CE-MS) and gas chromatography-MS (GC–MS).
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Metabolomics techniques have been used in the prediction or diagnosis of special clinical pattern of CKD-MBD. For instance, difference in metabolites can reflect difference in bone metabolism in CKD patients. A range of metabolites involved in protein synthesis, amino acid, energy, steroid hormone have been discovered to be associated with elevated iPTH in patients with end-stage renal disease (ESRD) using?LC-MS metabolic prefiling. Bone biopsy is the gold standard for diagnosis of different osteodystrophy. However, metabolites screened using NMR combining with demographical information may be comparable in their values to diagnose bone disease as bone biopsy. ethanol was associated with mineralization disorder, and low carnitine was seen in patients with low bone Dimethylsulfone, glycine, citrate, and N-acetylornithine could indicate bone turnover, low volume.1 Of note, L- carnitine has been widely used in hemodialysis patients as a beneficial supplement which has proved to significantly reduces oxidative and inflammatory stress, erythropoietin-resistant anemia, and comorbidities such as tiredness, impaired cognition, muscle weakness, myalgia, and muscle wasting. Whether it can be a target to treat osteodystrophy in CKD needs further investigation. The relationship between microbiomes and CKD has been hotspot for research for several years. Metabolomics indicate that gut microbiomes and its metabolites can regulate the bone metabolism by interacting with immune cells.2 The role of treating or modifying microbiomes in dealing with CKD-MBD are warranted in the future.
Proteomics
As the technique evolves, we are entering an era with more accurate multilevel proteomics testing.?Based on the hierarchy of the aimed proteins, proteomics could be classified into three categories:?bottom-up proteomics, top-down proteomics, and native proteomics. Integration of deep learning into proteomics profiling and analysis help make breakthroughs in techniques.
Several signal pathways (e.g. Wnt signaling, TGF- β, RANKL) play important roles in CKD-MBD. Using proteomics, proteins in different tissues or organs could be screened and linked with bone metabolism parameters. Denosumab targeting RANKL has been used in CKD patients with osteoporosis pushing us one more step to impede the progression of renal osteopathy. However, no single pathway can explain the whole view. We need to launch more studies integrating the information regarding interactions among inflammation, bone metabolism, and coagulation and anticoagulation system.
Genomics
With the development of large scale GWAS, many genetic signals associated with renal osteodystrophy and related traits have since been reported. However, identifying underlying gene responsible for these genetic associations, a prerequisite for drug targets, remains a challenge. "Osteocyte signature" has been entitled following the development of bone phenotyping and functional study models (e.g. knockout mice and zebrafish) to describe the facilitated characterization of bone disease provided by genomics. Based on the expanding "multi-omics" database resources, potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels leading to the discovery of signal pathways are studied.
Genome-wide association studies (GWAS) prompt understanding of the genetic determinants of circulating levels of 25-hydroxyvitamin D, calcium, phosphorus, fibroblast growth factor-23, parathyroid hormone, fetuin-A and osteoprotegerin. However, what remain to be answer are how kidney function impacts these processes and which biomarker, and whether certain genetic variant casts impact on kidney structure and functions. Mendelian randomization, known as a perfect instrumental variable, may help answer the questions.