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New Generation Biomarkers in Kidney Transplantation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 January 2023) | Viewed by 8458

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Dr. Cheng-Hsu Chen

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Guest Editor

Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan
Interests: tuberculosis; polymoavirus infection; CMV infection; post-transplant diabetes; fertility; offsprings health

Special Issue Information

Dear Colleagues,

Recent advances in surgical techniques, immunosuppressive regimens and transplant experience exchanges have provided excellent short-term renal graft survival, but the long-term outcomes have historically been unchanged. Approximately 40% of kidney transplants fail within ten years after transplantation, with immunological and non-immunological factors contributing to late allograft loss. Preformed and de novo donor-specific antibodies (DSAs) might cause chronic and acute antibody-mediated rejection (ABMR) and may also relate to tochronic and acute T cell-mediated rejection (TCMR); these clinically allogeneic immune processes often lead to cumulative graft injury and deterioration of graft function. In fact, non-immunological factors including DSAs’ original renal disease entities, age and gender, as well as cardiovascular diseases, infections, medications, adherence and malignancy, have contributed to the failure of kidney allografts. Consequently, the current development of advance cellular and molecular biotechnologies has allowed rapid detection of new biomarkers of infection or disease associated with chronic renal injury, though available therapeutic options are far from sufficient. Current research is directed towards understanding the updates and insights into the latest developments of promising novel knowledge for diagnosis and therapeutic interventions to promote long-term graft survival.

In this Special Issue, we welcome the submission of full reviews, original research articles, short communications and perspectives that cover, but are not limited to, the following topics:

Biomarkers for immune tolerance (miRNAs, or other surrogate markers);
Biomarkers for predicting kidney graft survival after acute or chronic rejection;
Future biomarkers (RNA profiling, or other surrogate markers) for infections in renal transplant recipients;
Oncology biomarkers and outcomes for renal transplant recipients.

Dr. Cheng-Hsu Chen
Guest Editor

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Published Papers (6 papers)

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Research

14 pages, 3627 KiB

Open AccessArticle

Urinary Biomarkers for Cell Cycle Arrest TIMP-2 and IGFBP7 for Prediction of Graft Function Recovery after Kidney Transplantation

by Anja Gäckler, Onurcan Ertasoglu, Hana Rohn, Justa Friebus-Kardash, Philipp-Christopher Ickerott, Oliver Witzke, Andreas Kribben, Bruno Vogt, Suzan Dahdal, Spyridon Arampatzis and Ute Eisenberger

Int. J. Mol. Sci. 2024, 25(8), 4169; https://doi.org/10.3390/ijms25084169 - 10 Apr 2024

Viewed by 514

Abstract

TIMP-2 and IGFBP7 have been identified and validated for the early detection of renal injury in critically ill patients, but data on recovery of allograft function after kidney transplantation (KTx) are scarce. In a prospective observational multicenter cohort study of renal transplant recipients, urinary [TIMP-2] × [IGFBP7] was evaluated daily from day 1 to 7 after KTx. Different stages of early graft function were defined: immediate graft function (IGF) (decrease ≥ 10% in serum creatinine (s-crea) within 24 h post KTx); slow graft function (SGF) (decrease in s-crea < 10% within 24 h post KTx); and delayed graft function (DGF) (any dialysis needed within the first week after KTx). A total of 186 patients were analyzed. [TIMP-2] × [IGFBP7] was significantly elevated as early as day 1 in patients with DGF compared to SGF and IGF. ROC analysis of [TIMP-2] × [IGFBP7] at day 1 post-transplant for event “Non-DGF” revealed a cut-off value of 0.9 (ng/mL)²/1000 with a sensitivity of 87% and a specificity of 71%. The positive predictive value for non-DGF was 93%. [TIMP-2] × [IGFBP7] measured at day 1 after KTx can predict early recovery of transplant function and is therefore a valuable biomarker for clinical decision making. Full article

(This article belongs to the Special Issue New Generation Biomarkers in Kidney Transplantation)

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14 pages, 8389 KiB

Open AccessArticle

Impact of Induction Immunosuppressants on T Lymphocyte Subsets after Kidney Transplantation: A Prospective Observational Study with Focus on Anti-Thymocyte Globulin and Basiliximab Induction Therapies

by Hyung Duk Kim, Hyunjoo Bae, Sojeong Yun, Hanbi Lee, Sang Hun Eum, Chul Woo Yang, Eun-Jee Oh and Byung Ha Chung

Int. J. Mol. Sci. 2023, 24(18), 14288; https://doi.org/10.3390/ijms241814288 - 19 Sep 2023

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Abstract

Induction immunosuppressive therapy for kidney transplant recipients (KTRs) primarily includes interleukin-2 receptor antagonists, such as basiliximab (BXM) or lymphocyte-depleting agents, and anti-thymocyte globulin (ATG). This study aimed to investigate their effects on T cell dynamics during the early post-transplantation period. This prospective observational study included 157 KTRs. Peripheral blood samples were collected from each patient within 5 days before and 4 and 12 weeks after transplantation. Flow cytometric analysis was performed to assess various T cell subsets whose changes were then analyzed. In the ATG group, CD4⁺ T cell expression decreased significantly compared with that in the BXM group. However, CD4⁺CD161⁺ and CD4⁺CD25⁺CD127low T cell expression levels increased significantly. In the CD8⁺ T cell subset, a decrease in CD8⁺CD28nullCD57⁺ and CD8⁺CCR7⁺ T cell expression was observed in the ATG group. However, among patients diagnosed with biopsy-proven acute rejection, T cell subset expression did not significantly differ relative to non-rejection cases. In conclusion, ATG induction therapy resulted in more pronounced changes in T lymphocyte subsets than BXM induction, with increased CD4⁺CD161⁺ and CD4⁺CD25⁺CD127low T cells and an early decrease in CD8⁺CD28nullCD57⁺ and CD8⁺CCR7⁺ T cells, some of which are associated with acute rejection. Full article

(This article belongs to the Special Issue New Generation Biomarkers in Kidney Transplantation)

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12 pages, 723 KiB

Open AccessCommunication

Urinary Biomarkers in a Living Donor Kidney Transplantation Cohort—Predictive Value on Graft Function

by G. J. Julia Huisman, Nora A. Spraakman, Jeroen V. Koomen, A. Marrit Talsma, Robert A. Pol, Stefan P. Berger, Henri G. D. Leuvenink, Michel M. R. F. Struys and Gertrude J. Nieuwenhuijs-Moeke

Int. J. Mol. Sci. 2023, 24(6), 5649; https://doi.org/10.3390/ijms24065649 - 15 Mar 2023

Cited by 1 | Viewed by 1429

Abstract

Early non-invasive detection and prediction of graft function after kidney transplantation is essential since interventions might prevent further deterioration. The aim of this study was to analyze the dynamics and predictive value of four urinary biomarkers: kidney injury molecule-1 (KIM-1), heart-type fatty acid binding protein (H-FABP), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in a living donor kidney transplantation (LDKT) cohort. Biomarkers were measured up to 9 days after the transplantation of 57 recipients participating in the VAPOR-1 trial. Dynamics of KIM-1, NAG, NGAL, and H-FABP significantly changed over the course of 9 days after transplantation. KIM-1 at day 1 and NAG at day 2 after transplantation were significant predictors for the estimated glomerular filtration rate (eGFR) at various timepoints after transplantation with a positive estimate (p < 0.05), whereas NGAL and NAG at day 1 after transplantation were negative significant predictors (p < 0.05). Multivariable analysis models for eGFR outcome improved after the addition of these biomarker levels. Several donor, recipient and transplantation factors significantly affected the baseline of urinary biomarkers. In conclusion, urinary biomarkers are of added value for the prediction of graft outcome, but influencing factors such as the timing of measurement and transplantation factors need to be considered. Full article

(This article belongs to the Special Issue New Generation Biomarkers in Kidney Transplantation)

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11 pages, 1078 KiB

Open AccessCommunication

Gender Differences in microRNA Expressions as Related to Long-Term Graft Function in Kidney Transplant Patients

by Sien-Yu Ko, Shang-Feng Tsai, Chia-Tien Hsu, Shih-Ting Huang, Ya-Wen Chuang, Tung-Min Yu, Ming-Ju Wu and Cheng-Hsu Chen

Int. J. Mol. Sci. 2022, 23(21), 12832; https://doi.org/10.3390/ijms232112832 - 24 Oct 2022

Cited by 3 | Viewed by 1344

Abstract

In recent studies, much has been discussed about biomarkers used in the evaluation of the transplanted graft function. However, there remains a lack of research regarding the long-term effects of microRNAs (miRNAs) on the different genders for kidney transplant (KTx) patients. In this study, we aim to assess the functions of miRNAs on long term outcomes of KTx patients by extracting differently expressed miRNAs between patients of normal graft function and graft dysfunction, while further analyzing their impact on the different genders. We analyzed the data of 40 patients who had received KTx for a period of more than ten years and included data regarding renal function, immuno-related markers and plasma miRNAs. Data were classified by gender for further studies. Twelve out of 17 females and 8 out of 23 males had undergone graft dysfunction. Renal function analysis showed significantly worse outcomes in the female patients. There were five differently expressed miRNAs between the female control group and female dysfunction group: miR-128-3p, miR-21-5p, miR-150-5p, miR-92a-3p and miR-15a-5p, and five between the male control group and male dysfunction group: miR-23a-3p, miR-126-3p, miR-142-3p, miR-223-3p and miR-26a-5p. Gender differences exist in incidences of kidney graft dysfunction, with male patients displaying better preservation in graft functions. Overall, these differently expressed miRNAs either enhance or suppress host immune responses. They can be predictive markers for graft survival and can also be important factors that lead to worse long term kidney graft function in females when compared to males. Full article

(This article belongs to the Special Issue New Generation Biomarkers in Kidney Transplantation)

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11 pages, 968 KiB

Open AccessArticle

Association between Circulating MicroRNAs (miR-21-5p, miR-20a-5p, miR-29b-3p, miR-126-3p and miR-101-3p) and Chronic Allograft Dysfunction in Renal Transplant Recipients

by Yu-Jen Chen, Chia-Tien Hsu, Shang-Feng Tsai and Cheng-Hsu Chen

Int. J. Mol. Sci. 2022, 23(20), 12253; https://doi.org/10.3390/ijms232012253 - 14 Oct 2022

Cited by 1 | Viewed by 1716

Abstract

Chronic allograft dysfunction (CAD) is a major condition affecting long-term kidney graft survival. Serum microRNA (miRNA) has been reported as a biomarker for various conditions of allograft injuries. The upregulation of miR-21 is the best-known miRNA change in graft tissue, urine and plasma. However, the correlation of plasma miR-21 with the severity of CAD remains unclear. In our study, 40 kidney transplantation recipients with late graft survival for more than 10 years were enrolled. The CAD group (n = 20) had either an eGFR between 15 to 60 mL/min or a biopsy-proved chronic allograft nephropathy or rejection. The control group (n = 20) had an eGFR ≥ 60 mL/min without proteinuria and hematuria for a consecutive 3 months before the study. We performed RNA sequencing to profile the miRNAs expression. There were six differentially expressed miRNAs in the CAD group. Among them, miR-21-5p and miR-101-3p were decreased, and miR-20a-5p was increased. We found that miR-21-5p, miR-20a-5p and miR-101-3p all participated in the TGF-beta pathway. We demonstrated that decreased miR-21-5p and miR-101-3p, and increased miR-20a-5p were the novel CAD-associated miRNAs in the TGF-beta pathway. These findings may pave the way for developing early prediction miRNAs biomarkers for CAD, and possibly developing therapeutic tools in the field of kidney transplantation. Full article

(This article belongs to the Special Issue New Generation Biomarkers in Kidney Transplantation)

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15 pages, 1681 KiB

Open AccessArticle

BK Polyomavirus bkv-miR-B1-5p: A Stable Micro-RNA to Monitor Active Viral Replication after Kidney Transplantation

by Baptiste Demey, Marine Bentz, Véronique Descamps, Virginie Morel, Catherine Francois, Sandrine Castelain, Francois Helle and Etienne Brochot

Int. J. Mol. Sci. 2022, 23(13), 7240; https://doi.org/10.3390/ijms23137240 - 29 Jun 2022

Cited by 9 | Viewed by 1829

Abstract

Background: Bkv-miR-B1-5p is a viral micro-RNA (miRNA) specifically produced during BK polyomavirus (BKPyV) replication. Recent studies have suggested using bkv-miR-B1-5p as a biomarker to monitor viral infection and predict complications in kidney transplant patients. To identify the technical limitations of this miRNA quantification in biological samples, knowledge of its stability and distribution in the extracellular compartment is necessary. Moreover, a proof of concept for using bkv-miR-B1-5p as a biomarker of active replication in chronic infection is still missing in the published literature. Methods: The stability of bkv-miR-B1-5p was evaluated in samples derived from cell cultures and in urine from BKPyV-infected kidney transplant recipients. The miRNA was quantified in different fractions of the extracellular compartment, including exosomes, and protein binding was evaluated. Finally, we developed an in vitro model for chronic culture of BKPyV clinical isolates to observe changes in the bkv-miR-B1-5p level during persistent infections. Results: Bkv-miR-B1-5p is a stable biomarker in samples from humans and in vitro experiments. Marginally associated with the exosomes, most of the circulating bkv-miR-B1-5p is bound to proteins, especially Ago2, so the miRNA quantification does not require specific exosome isolation. The bkv-miR-B1-5p level is predictable of viral infectivity, which makes it a potential specific biomarker of active BKPyV replication after kidney transplantation. Full article

(This article belongs to the Special Issue New Generation Biomarkers in Kidney Transplantation)

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