scholarly journals Urinary Cell mRNA Profiles Predictive of Human Kidney Allograft Status

2021 ◽  
pp. CJN.14010820
Author(s):  
Michelle L. Lubetzky ◽  
Thalia Salinas ◽  
Joseph E. Schwartz ◽  
Manikkam Suthanthiran
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Acute Rejection ◽  
Biopsy Specimen ◽  
Acute Cellular Rejection ◽  
Kidney Allograft ◽  
Antibody Mediated Rejection ◽  
Biopsy Specimens ◽  
Allograft Biopsy ◽  
Cellular Rejection

Immune monitoring of kidney allograft recipients and personalized therapeutics may help reach the aspirational goal of “one transplant for life.” The invasive kidney biopsy procedure, the diagnostic tool of choice, has become safer and the biopsy classification more refined. Nevertheless, biopsy-associated complications, interobserver variability in biopsy specimen scoring, and costs continue to be significant concerns. The dynamics of the immune repertoire make frequent assessments of allograft status necessary, but repeat biopsies of the kidney are neither practical nor safe. To address the existing challenges, we developed urinary cell mRNA profiling and investigated the diagnostic, prognostic, and predictive accuracy of absolute levels of a hypothesis-based panel of mRNAs encoding immunoregulatory proteins. Enabled by our refinements of the PCR assay and by investigating mechanistic hypotheses, our single-center studies identified urinary cell mRNAs associated with T cell–mediated rejection, antibody-mediated rejection, interstitial fibrosis and tubular atrophy, and BK virus nephropathy. In the multicenter National Institutes of Health Clinical Trials in Organ Transplantation-04, we discovered and validated a urinary cell three-gene signature of T-cell CD3 ε chain mRNA, interferon gamma inducible protein 10 (IP-10) mRNA, and 18s ribosomal RNA that is diagnostic of subclinical acute cellular rejection and acute cellular rejection and prognostic of acute cellular rejection and graft function. The trajectory of the signature score remained flat and below the diagnostic threshold for acute cellular rejection in the patients with no rejection biopsy specimens, whereas a sharp rise was observed during the weeks before the biopsy specimen that showed acute cellular rejection. Our RNA sequencing and bioinformatics identified kidney allograft biopsy specimen gene signatures of acute rejection to be enriched in urinary cells matched to acute rejection biopsy specimens. The urinary cellular landscape was more diverse and more enriched for immune cell types compared with kidney allograft biopsy specimens. Urinary cell mRNA profile–guided clinical trials are needed to evaluate their value compared with current standard of care.

Acute Rejection Following Kidney Transplantation: State-of-the-Art and Future Perspectives

2020 ◽  
Vol 26 (28) ◽  
pp. 3468-3496
Author(s):  
Emilio Rodrigo ◽  
Marcio F. Chedid ◽  
David San Segundo ◽  
Juan C.R. San Millán ◽  
Marcos López-Hoyos
Keyword(s):  
Kidney Transplantation ◽  
Acute Rejection ◽  
Rescue Therapy ◽  
Standard Of Care ◽  
Rejection Rate ◽  
New Drugs ◽  
High Dose ◽  
Current Standard ◽  
Antibody Mediated Rejection ◽  
Cellular Rejection

: Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. : According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

scholarly journals What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

2018 ◽  
Vol 14 (11) ◽  
pp. e722-e728 ◽  
Author(s):  
Katherine V. Ferry-Galow ◽  
Vivekananda Datta ◽  
Hala R. Makhlouf ◽  
John Wright ◽  
Bradford J. Wood ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Anticancer Agents ◽  
Biopsy Specimen ◽  
Tissue Quality ◽  
Tumor Biopsy ◽  
Time Investment ◽  
Biopsy Specimens ◽  
Oncology Clinical Trials ◽  
Specimen Quality ◽  
Academic Recognition

Purpose: Research biopsy specimens collected in clinical trials often present requirements beyond those of tumor biopsy specimens collected for diagnostic purposes. Research biopsies underpin hypothesis-driven drug development, pharmacodynamic assessment of molecularly targeted anticancer agents, and, increasingly, genomic assessment for precision medicine; insufficient biopsy specimen quality or quantity therefore compromises the scientific value of a study and the resources devoted to it, as well as each patient’s contribution to and potential benefit from a clinical trial. Methods: To improve research biopsy specimen quality, we consulted with other translational oncology teams and reviewed current best practices. Results: Among the recommendations were improving communication between oncologists and interventional radiologists, providing feedback on specimen sufficiency, increasing academic recognition and financial support for the time investment required by radiologists to collect and preserve research biopsy specimens, and improving real-time assessment of tissue quality. Conclusion: Implementing these recommendations at the National Cancer Institute’s Developmental Therapeutics Clinic has demonstrably improved the quality of biopsy specimens collected; more widespread dissemination of these recommendations beyond large clinical cancer centers is possible and will be of value to the community in improving clinical research and, ultimately, patient care.

Mild Acute Cellular Rejection Is Associated With Systemic Donor-Specific Regulatory and Conventional T Cell Responses

2015 ◽  
Vol 34 (4) ◽  
pp. S148
Author(s):  
J.R. Greenland ◽  
C.M. Wong ◽  
R. Ahuja ◽  
C. Uchida ◽  
J.A. Golden ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Acute Cellular Rejection ◽  
Cell Responses ◽  
Cellular Rejection

scholarly journals Diagnosis of Acute Cellular Rejection and Antibody-Mediated Rejection on Lung Transplant Biopsies: A Perspective From Members of the Pulmonary Pathology Society

2016 ◽  
Vol 141 (3) ◽  
pp. 437-444 ◽  
Author(s):  
Anja C. Roden ◽  
Dara L. Aisner ◽  
Timothy Craig Allen ◽  
Marie Christine Aubry ◽  
Roberto J. Barrios ◽  
...  
Keyword(s):  
Lung Transplant ◽  
Transbronchial Biopsy ◽  
Acute Cellular Rejection ◽  
Graft Dysfunction ◽  
Antibody Mediated Rejection ◽  
Triple Test ◽  
Pathologic Findings ◽  
Pulmonary Pathology ◽  
Donor Specific Antibodies ◽  
Cellular Rejection

Context.— The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. Objective.— To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. Data Sources.— Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). Conclusions.— Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

Sign in / Sign up

Export Citation Format

Share Document