Proteomics in Kidney Allograft Transplantation—Application of Molecular Pathway Analysis for Kidney Allograft Disease Phenotypic Biomarker Selection

Abstract

There is a need for accurate, robust, non-invasive methods to provide early diagnosis of graft lesions after kidney transplantation. A multitude of proteomic biomarkers for the major kidney allograft disease phenotypes defined by the BANFF classification criteria have been described in literature. None of these biomarkers have been established in the clinic. A key reason for this is the lack of clinical validation which is difficult, as even the gold standard of diagnosis, kidney biopsy, is often ambiguous. The semantic clustering by ReviGO on top of transcriptomic pathway analysis is evaluated to connect histological and transcriptomic kidney allograft disease characteristics with proteomic biomarker qualification. By using public data generated in microarray studies of kidney allograft tissue, biological processes and key molecules specifically associated with the different kidney allograft disease phenotypes are identified. Semantic clustering holds the promise to guide adaptation of proteomic marker panels to molecular pathology. This can support the development of noninvasive tests (e.g. in urine, by capillary electrophoresis mass spectrometry) that simultaneously detect diverse kidney allograft phenotypes with high accuracy and sensitivity.

Diagnosis of renal transplant rejection: Banff classification and beyond

“…The discovery and application of non-invasive molecular markers for effective diagnosis of renal transplant rejection are active fields of research [55][56][57]. Importantly, to develop a comprehensive approach, integration of tissue pathology assessment, transcriptomics, and urinary proteomics may be needed, particularly in cases of chronic TCMR [58]. Recently, the NanoString Banff consortium was launched to develop the nCounter Human Organ Transplant Panel to identify biomarkers of rejection, uncover the mechanisms behind tissue damage, and monitor immunosuppressive drug toxicity and infections using paraffin-embedded renal tissue [59].…”

Urinary Peptidomic Biomarkers in Kidney Diseases

“…In a recent review on proteomic markers for T-cell mediated rejection, use of the pathway-and enzyme reaction-related Reactome information resource revealed processes related to platelet degranulation, lipid digestion, keratan sulphate degradation, antigen presentation and interferon gamma signaling to be directly associated with the input proteins [58]. More recently, Marx et al [67] used a semantic clustering approach to evaluate the molecular pathway and biological processes specific for different forms of renal allograft disease, including T cell-mediated rejection, antibody-mediated rejection, intestinal fibrosis and tubular atrophy, and polyomavirus-associated nephropathy. By connecting histological and transcriptomic kidney allograft disease characteristics with proteomic biomarker qualification, this approach identified phenotype-specific pathways and associated key molecules that can be used as markers for a given phenotype [67].…”

“…More recently, Marx et al [67] used a semantic clustering approach to evaluate the molecular pathway and biological processes specific for different forms of renal allograft disease, including T cell-mediated rejection, antibody-mediated rejection, intestinal fibrosis and tubular atrophy, and polyomavirus-associated nephropathy. By connecting histological and transcriptomic kidney allograft disease characteristics with proteomic biomarker qualification, this approach identified phenotype-specific pathways and associated key molecules that can be used as markers for a given phenotype [67].…”

Proteomics for Clinical Assessment of Kidney Disease

“…As an example, laser dissection mass spectrometry is currently the best available option to characterize the nature of glomerular amyloidosis, a requirement for etiology‐targeted therapy . In this issue of PROTEOMICS—Clinical Applications, four manuscripts explore different aspects of clinical proteomics in the context of AKI, CKD, and kidney transplantation from a diagnostic and risk stratification point of view . In this regard, another major application of proteomics to kidney research, the identification of novel pathogenic pathways, is not specifically addressed …”