Rejection markers in kidney transplantation: do new technologies help children?

Abstract

Recent insights in allorecognition and graft rejection mechanisms revealed a more complex picture than originally considered, involving multiple pathways of both adaptive and innate immune response, supplied by efficient inflammatory synergies. Current pillars of transplant monitoring are serum creatinine, proteinuria, and drug blood levels, which are considered as traditional markers, due to consolidated experience, low cost, and widespread availability. The most diffuse immunological biomarkers are donor-specific antibodies, which are included in routine post-transplant monitoring in many centers, although with some reproducibility issues and interpretation difficulties. Confirmed abnormalities in these traditional biomarkers raise the suspicion for rejection and guide the indication for graft biopsy, which is still considered the gold standard for rejection monitoring. Rapidly evolving new “omic” technologies have led to the identification of several novel biomarkers, which may change the landscape of transplant monitoring should their potential be confirmed. Among them, urinary chemokines and measurement of cell-free DNA of donor origin are perhaps the most promising. However, at the moment, these approaches remain highly expensive and cost-prohibitive in most settings, with limited clinical applicability; approachable costs upon technology investments would speed their integration. In addition, transcriptomics, metabolomics, proteomics, and the study of blood and urinary extracellular vesicles have the potential for early identification of subclinical rejection with high sensitivity and specificity, good reproducibility, and for gaining predictive value in an affordable cost setting. In the near future, information derived from these new biomarkers is expected to integrate traditional tools in routine use, allowing identification of rejection prior to clinical manifestations and timely therapeutic intervention. This review will discuss traditional, novel, and invasive and non-invasive biomarkers, underlining their strengths, limitations, and present or future applications in children.

Immune monitoring in pediatric kidney transplant

“…Of note, early reports indicate that 17% of samples failed quality control, 73 a problem that highlights the methodological challenges of urinary mRNA, which tends to degrade without proper sample processing and storage even with high level of technical training. 74…”

“…Six hundred children are expected to be followed prospectively for 12 months with longitudinal urine testing and biopsies including for‐cause and surveillance. Of note, early reports indicate that 17% of samples failed quality control, 73 a problem that highlights the methodological challenges of urinary mRNA, which tends to degrade without proper sample processing and storage even with high level of technical training 74 …”

Contemporary Biomarkers for Renal Transplantation: A Narrative Overview

“…Drug level monitoring is an important biomarker for assessing the proper use of immunosuppressive drugs in transplant recipients. It is commonly performed for drugs such as tacrolimus, cyclosporine, everolimus, and sirolimus [ 195 ]. However, monitoring mycophenolic acid (MPA) using single-sample drug concentrations in the recipient’s blood immediately before the next dose is administered may not accurately reflect the overall drug exposure.…”

“…To overcome this limitation, MPA area under the curve estimation has been introduced as a more effective clinical tool. However, it requires multiple concentration samplings, which can be less practical, especially in pediatric patients [ 195 , 196 ].…”

Optical Imaging of Single Extracellular Vesicles: Recent Progress and Prospects

“…It should be noted that, since EV markers are not the focus of this review, the table here is not meant to be a complete list of all the markers reported in literature. We suggest readers to refer to other review articles for more thorough discussion of the various disease types and their potential EV markers. ,− …”