|
1
|
Futamura K, Tsujita M, Kosugi T, Ryuge A, Okada M, Hiramitsu T, Narumi S, Takeda A, Watarai Y, Morozumi K, Maruyama S. Urinary Basigin/CD147 is a useful marker of acute T cell-mediated rejection in kidney transplant recipients. Ren Fail 2025; 47:2479574. [PMID: 40125925 PMCID: PMC11934155 DOI: 10.1080/0886022x.2025.2479574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 02/23/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Acute T cell-mediated rejection (ATCMR) is a severe negative outcome of kidney transplantation; however, it currently has no reliable marker in Japan. METHODS This cross-sectional study was conducted at the Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 2016 to 2018 to determine whether plasma or urinary Basigin/CD147 is an effective marker of ATCMR. Plasma and urinary samples were obtained when episode graft biopsies were performed. RESULTS Forty-six kidney transplant recipients received graft biopsies. Three of them missed plasma and urinary samples and three in ATCMR were on postrejection treatment. Graft biopsy results revealed ATCMR in 12 of them, calcineurin inhibitor nephrotoxicity (CIN) in nine, chronic active antibody-mediated rejection (CAAMR) in nine, BK nephropathy, recurrence IgA nephropathy, necrotic glomerulonephritis, and infection-related glomerulonephritis in one each, and other complications in six. The urinary Basigin/CD147 levels of patients in the ATCMR group [759.4 (490.0, 843.0)] pg/gCre were significantly higher than the levels of patients in the CAAMR [247.0 (157.1, 288.8)] and CIN groups [379.1 (264.7, 456.7)] pg/gCre (p < 0.001). No statistical difference in plasma Basigin/CD147 levels was observed between those groups. At a urinary Basigin/CD147 of 631.5 µg/gCre, 75% sensitivity and 84% specificity with an area under the curve of 0.80 were attained for the diagnosis of graft rejection. CONCLUSION Urinary Basigin/CD147 may be a potential marker for ATCMR in kidney transplant recipients. Further studies will be needed to clarify the effectiveness of Basigin/CD147.
Collapse
Affiliation(s)
- Kenta Futamura
- Department of Kidney Disease Center, Transplant Nephrology and Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Makoto Tsujita
- Department of Kidney Disease Center, Transplant Nephrology and Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akihiro Ryuge
- Internal Medicine, Ryuge Internal Medicine Kamiotai Clinic, Nagoya, Japan
| | - Manabu Okada
- Department of Kidney Disease Center, Transplant Nephrology and Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Takahisa Hiramitsu
- Department of Kidney Disease Center, Transplant Nephrology and Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Shunji Narumi
- Department of Kidney Disease Center, Transplant Nephrology and Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Asami Takeda
- Department of Kidney Disease Center, Transplant Nephrology and Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | | | - Kunio Morozumi
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
2
|
Merhej T, El Fekih R, Azzi JR. Urinary biomarkers of kidney transplant rejection. Curr Opin Organ Transplant 2025; 30:195-200. [PMID: 40173008 DOI: 10.1097/mot.0000000000001217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
PURPOSE OF REVIEW Despite the introduction of many new immunosuppressive medications, allograft rejection remains a significant complication in transplantation. The use of "liquid biopsy" to evaluate allograft function and detect early rejection has recently become a prominent focus of investigation as it holds promise in providing noninvasive and immediate insights into the cellular and molecular makeup of the graft. RECENT FINDINGS In recent years, the introduction of molecular medicine along with the use of new technologies, including high-throughput techniques, has not only accelerated biomarker discovery but has also contributed to improving our understanding of the mechanisms underlying immune rejection. Genomics, transcriptomics, and metabolomics approaches, along with the increasing use of machine learning techniques, have paved the way for the discovery and development of novel biomarkers. SUMMARY Each year, there are hundreds of new biomarker discoveries in the publications. However, only a small fraction can be practically used as clinical tests or surrogate endpoints, receive FDA approval, and reach clinical application. Well designed and reproducible discovery and validation studies are rare and crucial. A contributing factor could be poor study design or quality of biospecimen repositories. In this review, we discuss urinary biomarkers of kidney allograft rejection that have shown promising findings but have yet to be successfully transitioned from bench to bedside.
Collapse
Affiliation(s)
- Tamara Merhej
- Renal Division, Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | |
Collapse
|
|
3
|
Seifert ME, Kho AT, Sheward L, Rodig N, Goldberg S, Diehl M, Zurakowski D, Mannon RB, Dharnidharka VR, Bestard O, Blydt-Hansen TD, Briscoe DM. Combination Automated Microfluidics Measurement of Urine C-C Motif Ligand 2, CXC-Motif Chemokine 9, CXC-Motif Chemokine 10, and Vascular Endothelial Growth Factor A for Monitoring Patients with a Kidney Transplant. Clin J Am Soc Nephrol 2025; 20:719-732. [PMID: 40067364 PMCID: PMC12097184 DOI: 10.2215/cjn.0000000666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 03/06/2025] [Indexed: 05/09/2025]
Abstract
Key Points Combining urine C-C motif ligand 2, CXC-motif chemokine 9, CXC-motif chemokine 10, and vascular endothelial growth factor A identifies stable transplant recipients without biopsy-proven acute rejection with >75% specificity and 94% negative predictive value. Measuring four urine analytes in combination using an automated platform is highly efficient (<70 minutes) and reproducible across three independent sites. Automated urine analyte measurement provides critical decision support and outperforms eGFR measurements alone for post-transplantation monitoring. Background Recent studies indicate that up to 36% of pediatric and adult kidney transplant recipients with stable serum creatinine levels will have acute rejection detected on surveillance biopsy. The purpose of this study was to develop and validate a risk algorithm for identifying low- and high-risk patients using a novel automated platform that simultaneously measures urinary C-C motif ligand 2 (CCL2), CXC-motif chemokine 9 (CXCL9), CXC-motif chemokine 10 (CXCL10), and vascular endothelial growth factor A (VEGF-A) with high precision. Methods We designed a multicenter observational study to evaluate the performance of urinary CCL2, CXCL9, CXCL10, and VEGF-A in a training set of 517 banked samples collected at the time of surveillance or indication kidney biopsies from both adult and pediatric recipients. Risk algorithms combining all four analytes were developed in the training set and subsequently validated in three laboratory sites in two additional pediatric cohorts (N =174). Results The automated platform had remarkably high throughput, generating reproducible results in 60–70 minutes. Analysis was initially performed in the training set (N =517), which included biopsies read as normal (N =330), acute rejection (N =92), or borderline rejection (N =95). We found that each biomarker independently discriminated normal biopsies versus those with acute rejection (P < 10−5). A risk algorithm using all four biomarkers (score4) had excellent diagnostic performance for acute rejection in both for-cause and surveillance biopsies performed on patients with stable GFRs, outperforming any individual biomarker as well as estimated GFR assessments. Validation assays performed in the two additional pediatric cohorts in three laboratory sites demonstrated a robust correlation of results; score4 retained excellent diagnostic performance (75% specificity and 92% negative predictive value). Conclusions Automated measurements of urine CCL2, CXCL9, CXCL10, and VEGF-A can distinguish kidney transplant recipients at low versus high risk of rejection. We suggest that this assay can advantage clinical decision making in routine post-transplant monitoring because of its low cost, rapid throughput, and operator independence.
Collapse
Affiliation(s)
| | - Alvin T. Kho
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Lea Sheward
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nancy Rodig
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Sarah Goldberg
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Margaret Diehl
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - David Zurakowski
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Vikas R. Dharnidharka
- Washington University School of Medicine, St. Louis, Missouri; Current Address: Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | | | | | - David M. Briscoe
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
4
|
El Fekih R, Franzen K, Hurley J, Haynes BC, Merhej T, Alghamdi A, Hallmark E, Xing S, Kumar S, Choi J, Solhjou Z, Deban C, Saad A, Halawi A, Younis N, Cashman K, Dagher M, Eskandari SK, Al Chaar S, Rennke H, Weins A, Abdi R, Chandraker A, Markmann JF, Safa K, Riella LV, McFaul M, Ventura C, Vlassov AV, Formica R, Macedo C, Skog J, Azzi JR. An Exosomal mRNA Urine Test for Detection and Risk Stratification of Human Kidney Transplant Rejection. Kidney Int Rep 2025; 10:1131-1142. [PMID: 40303229 PMCID: PMC12034883 DOI: 10.1016/j.ekir.2025.01.036] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/27/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction We recently discovered 2 urinary exosomal mRNA signatures to identify and differentiate T-cell-mediated rejection (TCMR) from antibody-mediated rejection (ABMR) in kidney transplant recipients. Here, we developed Exosome Transplant Rejection Urine (ExoTRU), a urinetest based on a 4-gene signature from the previous discovery cohort, showed its clinical utility in a new cohort of kidney transplant recipients undergoing clinically indicated biopsies, and validated it through a separate laboratory in an independent-cohort of patients. Methods A workflow suited for clinical laboratories was developed, allowing for smaller urine volumes and widely standardized qPCR instrumentation. A total of 226 urine samples from 214 patients were paired with clinically indicated biopsies. Urinary exosomal mRNAs levels were evaluated for previously defined targets. Results Four mRNAs (IL32, B2M, CXCL11, and PGK1) performed well in distinguishing biopsies with rejection or significant inflammation from those without inflammation, achieving 94% sensitivity, 62% positive predictive value, and 52% specificity. Patients who tested positive by the signature but negative by biopsy were nearly twice as likely to experience adverse outcomes in the 5-year follow-up period, including subsequent rejection, thereby showing the limitations of kidney biopsies and the prognostic potential of molecular signatures. The evaluation of an independent validation cohort showed similar performance, achieving an area under the curve (AUC) of 0.838. Another 6-gene signature distinguished TCMR from ABMR, with an AUC of 0.756. Conclusion Exosomal mRNA gene signatures identified patients with different stages and classes of rejection, including early stage and significant inflammation, enabling improved decision-making and patient management and reducing unnecessary biopsies by 45%. This represents a potential tool for risk stratification based on poor outcomes in patients with positive signatures.
Collapse
Affiliation(s)
- Rania El Fekih
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kurt Franzen
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - James Hurley
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - Brian C. Haynes
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
- Asuragen, a Bio-Techne brand, Austin, Texas, USA
| | - Tamara Merhej
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Areej Alghamdi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Shuran Xing
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - Sonia Kumar
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - John Choi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Zhabiz Solhjou
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christa Deban
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anis Saad
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ahmad Halawi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nour Younis
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Katherine Cashman
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Maribel Dagher
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Siawosh K. Eskandari
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Soltan Al Chaar
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Helmut Rennke
- Pathology Department, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Astrid Weins
- Pathology Department, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Reza Abdi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anil Chandraker
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - James F. Markmann
- Division of Transplant Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kassem Safa
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Leonardo V. Riella
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Matt McFaul
- Thermo Fisher Scientific, West Hills, California, USA
| | - Chris Ventura
- Thermo Fisher Scientific, West Hills, California, USA
| | | | - Richard Formica
- Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Camila Macedo
- Thomas Starzl E. Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Johan Skog
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - Jamil R. Azzi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
5
|
Yang H, Chen Y, He J, Li Y, Feng Y. Advances in the diagnosis of early biomarkers for acute kidney injury: a literature review. BMC Nephrol 2025; 26:115. [PMID: 40045274 PMCID: PMC11884078 DOI: 10.1186/s12882-025-04040-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/21/2025] [Indexed: 03/09/2025] Open
Abstract
Acute kidney injury (AKI) is a critical condition with diverse manifestations and variable outcomes. Its diagnosis traditionally relies on delayed indicators such as serum creatinine and urine output, making early detection challenging. Early identification is essential to improving patient outcomes, driving the need for novel biomarkers. Recent advancements have identified promising biomarkers across various biological processes. Tubular injury markers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and liver-type fatty acid-binding protein (L-FABP), offer insights into early tubular damage. Inflammatory and repair-associated biomarkers, such as interleukin-18 (IL-18), monocyte chemotactic protein-1 (MCP-1), osteopontin (OPN), and C-C motif chemokine ligand 14 (CCL14), reflect ongoing injury and recovery processes. Additionally, stress and repair markers like tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP-7), alongside filtration markers such as cystatin C (CysC) and proenkephalin (PenKid®) e.tal, further enhance diagnostic precision. Oxidative stress-related markers, including Superoxide Dismutase 1 (SOD1), also contribute valuable information. Emerging candidates, such as microRNAs, soluble urokinase plasminogen activator receptor (SuPAR), and chitinase-3-like protein 1 (CHI3L1), hold substantial promise for AKI detection and prognosis. This review summarizes the progress in AKI biomarker research, highlighting their clinical utility and exploring their potential to refine early diagnosis and management strategies. These findings offer a new perspective for integrating novel biomarkers into routine clinical practice, ultimately improving AKI care.
Collapse
Affiliation(s)
- Hongsha Yang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Yanqin Chen
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Jiajia He
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Yi Li
- Department of Nephrology, Institute of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Centre for Kidney Diseases, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yunlin Feng
- Department of Nephrology, Institute of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Centre for Kidney Diseases, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| |
Collapse
|
|
6
|
Westphal SG, Mannon RB. Biomarkers of Rejection in Kidney Transplantation. Am J Kidney Dis 2025; 85:364-374. [PMID: 39419272 PMCID: PMC11846701 DOI: 10.1053/j.ajkd.2024.07.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/02/2024] [Accepted: 07/26/2024] [Indexed: 10/19/2024]
Abstract
Alloimmune injury is a major cause of long-term kidney allograft failure whether due to functionally stable (subclinical) or overt clinical rejection. These episodes may be mediated by immune cells (cellular rejection) or alloantibody (antibody-mediated rejection). Early recognition of immune injury is needed for timely appropriate intervention to maintain graft functional viability. However, the conventional measure of kidney function (ie, serum creatinine) is insufficient for immune monitoring due to limited sensitivity and specificity for rejection. As a result, there is need for biomarkers that more sensitively detect the immune response to the kidney allograft. Recently, several biomarkers have been clinically implemented into the care of kidney transplant recipients. These biomarkers attempt to achieve multiple goals including (1) more sensitive detection of clinical and subclinical rejection, (2) predicting impending rejection, (3) monitoring for the adequacy of treatment response, and (4) facilitating personalized immunosuppression. In this review, we summarize the findings to date in commercially available biomarkers, along with biomarkers approaching clinical implementation. While we discuss the analytical and clinical validity of these biomarkers, we identify the challenges and limitations to widespread biomarker use, including the need for biomarker-guided prospective studies to establish evidence of clinical utility of these new assays.
Collapse
Affiliation(s)
- Scott G Westphal
- Division of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Medical Service, Nebraska Western Iowa Veterans Affairs Health Care System, Omaha, Nebraska
| | - Roslyn B Mannon
- Medical Service, Nebraska Western Iowa Veterans Affairs Health Care System, Omaha, Nebraska.
| |
Collapse
|
|
7
|
Gupta G, Athreya A, Kataria A. Biomarkers in Kidney Transplantation: A Rapidly Evolving Landscape. Transplantation 2025; 109:418-427. [PMID: 39020463 DOI: 10.1097/tp.0000000000005122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/19/2024]
Abstract
The last decade has seen an explosion in clinical research focusing on the use of noninvasive biomarkers in kidney transplantation. Much of the published literature focuses on donor-derived cell-free DNA (dd-cfDNA). Although initially studied as a noninvasive means of identifying acute rejection, it is now clear that dd-cfDNA is more appropriately described as a marker of severe injury and irrespective of the etiology, elevated dd-cfDNA ≥0.5% portends worse graft outcomes. Blood gene expression profiling is also commercially available and has mostly been studied in the context of early identification of subclinical rejection, although additional data is needed to validate these findings. Torque teno virus, a ubiquitous DNA virus, has emerged as a biomarker of immunosuppression exposure as peripheral blood Torque teno virus copy numbers might mirror the intensity of host immunosuppression. Urinary chemokine tests including C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 have recently been assessed in large clinical trials and hold promising potential for early diagnosis of both subclinical and acute rejection, as well as, for long-term prognosis. Urinary cellular messenger RNA and exosome vesicular RNA based studies require additional validation. Although current data does not lend itself to conclusion, future studies on multimodality testing may reveal the utility of serial surveillance for individualization of immunosuppression and identify windows of opportunity to intervene early and before the irreversible allograft injury sets in.
Collapse
Affiliation(s)
- Gaurav Gupta
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Akshay Athreya
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Ashish Kataria
- Division of Nephrology, Medical College of Georgia, Augusta, GA
| |
Collapse
|
|
8
|
Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
Collapse
Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
| |
Collapse
|
|
9
|
Salvadori M, Rosso G. New biomarkers in kidney transplant. GIORNALE DI CLINICA NEFROLOGICA E DIALISI 2024; 36:83-86. [DOI: 10.33393/gcnd.2024.3352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Recently, new interesting and important novel biomarkers have allowed the evidence based medicine to move to a new field called precision medicine. In particular, this apply to organ transplantation and to the diagnosis of rejection.
Among these novel biomarkers are the study of donor-derived cell-free DNA when present in the blood of the recipients, the study of gene expression profiling again in the recipient, and the study of several urinary cytokines. All these novel biomarkers have several advantages over the old biomarkers. Indeed, they are non-invasive, are able to detect renal damage before the appearance of histological abnormalities, and are able to distinguish antibody-mediated rejection from cell-mediated rejection. The aim of this study is to identify the most recent findings on these biomarkers and to describe their utility and their limitations in particular in the field of kidney acute rejection.
Collapse
|
|
10
|
Ruan DF, Fribourg M, Yuki Y, Park YH, Martin MP, Yu H, Kelly GC, Lee B, de Real RM, Lee R, Geanon D, Kim-Schulze S, Chun N, Cravedi P, Carrington M, Heeger PS, Horowitz A. High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction. JCI Insight 2024; 9:e185687. [PMID: 39388279 PMCID: PMC11601574 DOI: 10.1172/jci.insight.185687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024] Open
Abstract
Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.
Collapse
Affiliation(s)
- Dan Fu Ruan
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
| | - Miguel Fribourg
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yuko Yuki
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Yeon-Hwa Park
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Maureen P. Martin
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Haocheng Yu
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
| | - Geoffrey C. Kelly
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Brian Lee
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ronaldo M. de Real
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Rachel Lee
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Daniel Geanon
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Seunghee Kim-Schulze
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Nicholas Chun
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paolo Cravedi
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Mary Carrington
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Peter S. Heeger
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Amir Horowitz
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
| |
Collapse
|
|
11
|
Shankaranarayanan D, Mantri M, Lagman M, Li C, Sharma VK, Muthukumar T, Xiang JZ, De Vlaminck I, Machaca K, Suthanthiran M. Blockade of store-operated calcium entry by BTP2 preserves anti-inflammatory gene expression in human peripheral blood mononuclear cells. Hum Immunol 2024; 85:111144. [PMID: 39332042 PMCID: PMC11637971 DOI: 10.1016/j.humimm.2024.111144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/29/2024] [Accepted: 09/11/2024] [Indexed: 09/29/2024]
Abstract
Store-operated calcium entry (SOCE) is essential for cellular signaling. Earlier studies of the pyrazole derivative BTP2, an efficient inhibitor SOCE, identified that SOCE blockade suppresses proinflammatory gene expression. The impact of SOCE blockade on gene expression at the whole transcriptome level, however, is unknown. To fill this gap, we performed RNA sequencing (RNA-seq) and investigated at the whole transcriptome level the effect of BTP2 on gene expression in human peripheral blood mononuclear cells signaled with phytohemagglutinin. Our global gene expression analysis identified that SOCE blockade spares activation-induced expression of anti-inflammatory genes (e.g., IL10, TGFB1, FOXP3, and CTLA4) whereas the induced expression of proinflammatory genes such as IFNG and cytopathic genes such as GZMB are inhibited. We validated the differential expression of immunoregulatory genes identified by RNA-seq using preamplification-enhanced RT-qPCR assays. Because IL-2/IL2RA interaction is essential for T cell clonal expansion, we investigated and confirmed that BTP2 inhibits IL2RA expression at the protein level using multiparameter flow cytometry. Our elucidation that SOCE blockade spares activation-induced expression of anti-inflammatory genes while blocking pro-inflammatory gene expression suggests that SOCE blockers may represent a novel class of immunoregulatory drugs of value for treating autoimmune disease states and organ transplantation.
Collapse
Affiliation(s)
- Divya Shankaranarayanan
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA; Department of Transplantation Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA
| | - Madhav Mantri
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Mila Lagman
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Carol Li
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Vijay K Sharma
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Thangamani Muthukumar
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA; Department of Transplantation Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA
| | - Jenny Z Xiang
- Genomics Resources Core Facility, Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA
| | - Iwijn De Vlaminck
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Khaled Machaca
- Calcium Signaling Group, Research Department, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Manikkam Suthanthiran
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA; Department of Transplantation Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA.
| |
Collapse
|
|
12
|
Park BH, Kil SY, Kim YN, Shin HS, Jung Y, Rim H. Kidney transplantation in the elderly. Korean J Intern Med 2024; 39:875-881. [PMID: 39444336 PMCID: PMC11569922 DOI: 10.3904/kjim.2024.089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/11/2024] [Accepted: 05/27/2024] [Indexed: 10/25/2024] Open
Abstract
Interest in kidney transplant studies in the elderly population is increasing as more research has been conducted on the immune system. With this review, we hope to encourage the need for research on kidney transplantation in the elderly.
Collapse
Affiliation(s)
- Byung Hwa Park
- Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Song Yi Kil
- Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Ye Na Kim
- Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Ho Sik Shin
- Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Yeonsoon Jung
- Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Hark Rim
- Division of Nephrology, Department of Internal Medicine, Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| |
Collapse
|
|
13
|
Barbir EB, Abdulmoneim S, Dudek AZ, Kukla A. Immune Checkpoint Inhibitor Therapy for Kidney Transplant Recipients - A Review of Potential Complications and Management Strategies. Transpl Int 2024; 37:13322. [PMID: 39479217 PMCID: PMC11521864 DOI: 10.3389/ti.2024.13322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 10/01/2024] [Indexed: 11/02/2024]
Abstract
Immune checkpoint inhibitor (ICI) therapy has enabled a paradigm shift in Oncology, with the treatment of metastatic cancer in certain tumor types becoming akin to the treatment of chronic disease. Kidney transplant recipients (KTR) are at increased risk of developing cancer compared to the general population. Historically, KTR were excluded from ICI clinical trials due to concern for allograft rejection and decreased anti-tumor efficacy. While early post-marketing data revealed an allograft rejection risk of 40%-50%, 2 recent small prospective trials have demonstrated lower rates of rejection of 0%-12%, suggesting that maintenance immunosuppression modification prior to ICI start modulates rejection risk. Moreover, objective response rates induced by ICI for the treatment of advanced or metastatic skin cancer, the most common malignancy in KTR, have been comparable to those achieved by immune intact patients. Non-invasive biomarkers may have a role in risk-stratifying patients before starting ICI, and monitoring for rejection, though allograft biopsy is required to confirm diagnosis. This clinically focused review summarizes current knowledge on complications of ICI use in KTR, including their mechanism, risk mitigation strategies, non-invasive biomarker use, approaches to treatment of rejection, and suggestions for future directions in research.
Collapse
Affiliation(s)
- Elena Bianca Barbir
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | | | - Arkadiusz Z. Dudek
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States
| | - Aleksandra Kukla
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| |
Collapse
|
|
14
|
Mačionienė E, Simanavičius M, Vitkauskaitė M, Vickienė A, Staučė R, Vinikovas A, Miglinas M. Urinary Chemokines CXCL9 and CXCL10 Are Non-Invasive Biomarkers of Kidney Transplant Rejection. Ann Transplant 2024; 29:e944762. [PMID: 39402819 PMCID: PMC11490196 DOI: 10.12659/aot.944762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Rejection is the main cause of kidney allograft failure, and kidney biopsy is the criterion standard method to diagnose it. However, non-invasive techniques to detect kidney transplant rejection are necessary. This study aimed to evaluate urinary chemokines CXCL9 and CXCL10 as potential biomarkers of kidney transplant rejection and to analyze chemokine association with allograft prognosis. MATERIAL AND METHODS We collected 117 urine samples from kidney transplant recipients undergoing allograft biopsy. CXCL9 and CXCL10 levels were measured by ELISA and the ratio to urine creatinine was calculated. Histology and other clinical data were collected from medical records. RESULTS The diagnostic performance of urinary CXCL9/cre in discriminating rejection from all other histological groups showed an ROC AUC value of 0.728 (95% CI 0.632-0.824, p<0.001), and a cut-off value 0.11 ng/mmol had the best sensitivity (76.9%) and specificity (73.1%). The ability of CXCL10/cre to discriminate transplant rejection from all other histological groups had ROC AUC value 0.73 (95% CI 0.63-0.84, P<0.001), the cut-off value 0.42 ng/mmol with best sensitivity (71.4%) and specificity (84.6%). CXCL9 and CXCL10 levels were also increased in patients with polyoma BK virus, recurrent AA amyloidosis, and thrombotic microangiopathy. Patients with higher CXCL9/cre (≥0.11 ng/mmol) and CXCL10/cre (≥0.42 ng/mmol) levels were at increased risk of transplant progression to ESRD (HR 3.25, 95% CI=1.27-8.36, P=0.01), irrespective of serum creatinine at the time of biopsy. CONCLUSIONS Urinary CXCL9/cre and CXCL10/cre were able to distinguished between patients with transplant rejection and those without rejection. High levels of urinary CXCL9/cre and CXCL10/cre were associated with worse allograft survival.
Collapse
Affiliation(s)
- Ernesta Mačionienė
- Institute of Clinical Medicine, Gastroenterology, Nephro-Urology and Surgery Clinic, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Martynas Simanavičius
- Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Monika Vitkauskaitė
- Institute of Clinical Medicine, Gastroenterology, Nephro-Urology and Surgery Clinic, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Alvita Vickienė
- Institute of Clinical Medicine, Gastroenterology, Nephro-Urology and Surgery Clinic, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Roberta Staučė
- Nephrology Center, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Artūras Vinikovas
- Nephrology Center, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Marius Miglinas
- Institute of Clinical Medicine, Gastroenterology, Nephro-Urology and Surgery Clinic, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| |
Collapse
|
|
15
|
Tinel C, Sauvaget V, Aouni L, Lamarthée B, Terzi F, Legendre C, Rabant M, Anglicheau D. Transforming kidney transplant monitoring with urine CXCL9 and CXCL10: practical clinical implementation. Sci Rep 2024; 14:20357. [PMID: 39223175 PMCID: PMC11369285 DOI: 10.1038/s41598-024-70390-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
In kidney transplant recipients, urine CXCL9 and CXCL10 (uCXCL9/10) chemokines have reached a sufficiently high level of evidence to be recommended by the European Society of Organ Transplantation for the monitoring of immune quiescence. To assess the risk of acute rejection (AR), the advantage of uCXCL9/10 is their cost-effectiveness and their high diagnostic performance. Here, we evaluated the feasibility of a next-generation immunoassay for quantifying uCXCL9/10 levels. It demonstrated high efficiency with minimal workflow and a 90-min time to result. Preanalytical studies indicated stability of uCXCL9/10 levels and analytical studies confirmed excellent linearity and precision. In a cohort of 1048 samples collected at biopsy, the results correlated significantly with ELISA quantification and were integrated into a previously validated 8-parameter urine chemokine model. The next generation immunoassay achieved an accuracy of 0.84 for AR diagnosis. This study validates this technology as a robust, locally available and unexpensive platform and marks a significant step towards the widespread implementation of uCXCL9/10, for immune quiescence monitoring. Therefore, we developed an open-access web application using uCXCL9/10 to calculate AR risk and improve clinical decision-making to perform biopsy, ushering in a new era in kidney transplantation, where personalized, data-driven care becomes the norm.
Collapse
Affiliation(s)
- Claire Tinel
- Necker-Enfants Malades Institute, Inserm U1151, Paris Cité University, Paris, France.
- Department of Nephrology and Kidney Transplantation, Dijon University Hospital, Dijon, France.
| | - Virginia Sauvaget
- Necker-Enfants Malades Institute, Inserm U1151, Paris Cité University, Paris, France
| | - Laïla Aouni
- Department of Nephrology and Kidney Transplantation, Necker Hospital, APHP, Paris, France
| | - Baptiste Lamarthée
- University of Franche-Comté, UBFC, EFS, Inserm, UMR RIGHT, Besançon, France
| | - Fabiola Terzi
- Necker-Enfants Malades Institute, Inserm U1151, Paris Cité University, Paris, France
| | - Christophe Legendre
- Department of Nephrology and Kidney Transplantation, Necker Hospital, APHP, Paris, France
| | - Marion Rabant
- Necker-Enfants Malades Institute, Inserm U1151, Paris Cité University, Paris, France
- Pathology Department, Necker Hospital, APHP, Paris, France
| | - Dany Anglicheau
- Necker-Enfants Malades Institute, Inserm U1151, Paris Cité University, Paris, France
- Department of Nephrology and Kidney Transplantation, Necker Hospital, APHP, Paris, France
| |
Collapse
|
|
16
|
Ettenger RB, Seifert ME, Blydt-Hansen T, Briscoe DM, Holman J, Weng PL, Srivastava R, Fleming J, Malekzadeh M, Pearl M. Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices. Pediatr Transplant 2024; 28:e14836. [PMID: 39147695 DOI: 10.1111/petr.14836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024]
Abstract
INTRODUCTION The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION ClinicalTrials.gov: NCT03719339.
Collapse
Affiliation(s)
- Robert B Ettenger
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michael E Seifert
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Tom Blydt-Hansen
- Multi-Organ Transplant Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - David M Briscoe
- Division of Nephrology, Department of Pediatrics Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John Holman
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Patricia L Weng
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Rachana Srivastava
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - James Fleming
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Mohammed Malekzadeh
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Meghan Pearl
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| |
Collapse
|
|
17
|
Singampalli KL, Neal - Harris C, Yee C, Lin JS, Lillehoj PB. Highly Reusable Electrochemical Immunosensor for Ultrasensitive Protein Detection. ADVANCED SENSOR RESEARCH 2024; 3:2400004. [PMID: 39640072 PMCID: PMC11617009 DOI: 10.1002/adsr.202400004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Indexed: 12/07/2024]
Abstract
The detection and quantification of protein biomarkers in bodily fluids is important for many clinical applications, including disease diagnosis and health monitoring. Current techniques for ultrasensitive protein detection, such as enzyme-linked immunosorbent assay (ELISA) and electrochemical sensing, involve long incubation times (1.5-3 hr) and rely on single-use sensing electrodes which can be costly and generate excessive waste. This work demonstrates a reusable electrochemical immunosensor employing magnetic nanoparticles (MNPs) and dually labeled gold nanoparticles (AuNPs) for ultrasensitive measurements of protein biomarkers. As proof of concept, this platform was used to detect C-X-C motif chemokine ligand 9 (CXCL9), a biomarker associated with kidney transplant rejection, immune nephritis from checkpoint inhibitor therapy, and drug-associated acute interstitial nephritis, in human urine. The sensor successfully detected CXCL9 at concentrations as low as 27 pg/mL within ~1 hr. This immunosensor was also adapted onto a handheld smartphone-based diagnostic device and used for measurements of CXCL9, which exhibited a lower limit of detection of 65 pg/mL. Lastly, we demonstrate that the sensing electrodes can be reused for at least 100 measurements with a negligible loss in analytical performance, reducing the costs and waste associated with electrochemical sensing.
Collapse
Affiliation(s)
- Kavya L. Singampalli
- Department of Bioengineering, Rice University, Houston, TX, 77030, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, 77030, USA
| | | | - Cassian Yee
- Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jamie S. Lin
- Section of Nephrology, Division of Internal Medicine, UT MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Peter B. Lillehoj
- Department of Bioengineering, Rice University, Houston, TX, 77030, USA
- Department of Mechanical Engineering, Rice University, Houston, TX, 77005, USA
| |
Collapse
|
|
18
|
Rroji M, Figurek A, Spasovski G. Advancing kidney transplant outcomes: the role of urinary proteomics in graft function monitoring and rejection detection. Expert Rev Proteomics 2024; 21:297-316. [PMID: 39133121 DOI: 10.1080/14789450.2024.2389829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 06/15/2024] [Accepted: 07/30/2024] [Indexed: 08/13/2024]
Abstract
INTRODUCTION Kidney transplantation significantly improves the lives of those with end-stage kidney disease, offering best alternative to dialysis. However, transplant success is threatened by the acute and chronic rejection mechanisms due to complex immune responses against the new organ. AREAS COVERED The ongoing research into biomarkers holds promise for revolutionizing the early detection and monitoring of the graft health. Liquid biopsy techniques offer a new avenue, with several diagnostic, predictive, and prognostic biomarkers showing promise in detecting and monitoring kidney diseases and an early and chronic allograft rejection. EXPERT OPINION Evaluating the protein composition related to kidney transplant results could lead to identifying biomarkers that provide insights into the graft functionality. Non-invasive proteomic biomarkers can drastically enhance clinical outcomes and change the way how kidney transplants are evaluated for patients and physicians if they succeed in this transition. Hence, the advancement in proteomic technologies, leads toward a significant improvement in understanding of the protein markers and molecular mechanisms linked to the outcomes of kidney transplants. However, the road from discovery to the use of such proteins in clinical practice is long, with a need for continuous validation and beyond the singular research team with comprehensive infrastructure and across research groups collaboration.
Collapse
Affiliation(s)
- Merita Rroji
- Faculty of Medicine, University Department of Nephrology, University of Medicine Tirana, Tirana, Albania
| | - Andreja Figurek
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Goce Spasovski
- Medical Faculty, University Department of Nephrology, University of Skopje, Skopje, Macedonia
| |
Collapse
|
|
19
|
Pan X, Peng J, Zhu R, An N, Pei J. Non-invasive biomarkers of acute rejection in pediatric kidney transplantation: New targets and strategies. Life Sci 2024; 348:122698. [PMID: 38710278 DOI: 10.1016/j.lfs.2024.122698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/17/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
Kidney transplantation is the preferred treatment for pediatric end-stage renal disease. However, pediatric recipients face unique challenges due to their prolonged need for kidney function to accommodate growth and development. The continual changes in the immune microenvironment during childhood development and the heightened risk of complications from long-term use of immunosuppressive drugs. The overwhelming majority of children may require more than one kidney transplant in their lifetime. Acute rejection (AR) stands as the primary cause of kidney transplant failure in children. While pathologic biopsy remains the "gold standard" for diagnosing renal rejection, its invasive nature raises concerns regarding potential functional impairment and the psychological impact on children due to repeated procedures. In this review, we outline the current research status of novel biomarkers associated with AR in urine and blood after pediatric kidney transplantation. These biomarkers exhibit superior diagnostic and prognostic performance compared to conventional ones, with the added advantages of being less invasive and highly reproducible for long-term graft monitoring. We also integrate the limitations of these novel biomarkers and propose a refined monitoring model to optimize the management of AR in pediatric kidney transplantation.
Collapse
Affiliation(s)
- Xingyu Pan
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Jinpu Peng
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Rong Zhu
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Nini An
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Jun Pei
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550002, China.
| |
Collapse
|
|
20
|
Salvadori M, Rosati A, Rosso G. Evolving Biomarkers in Kidney Transplantation. TRANSPLANTOLOGY 2024; 5:116-128. [DOI: 10.3390/transplantology5030012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Precision medicine is mainly based on reliable and noninvasive biomarkers. The aim of this review was to describe the newest biomarkers in the field of kidney transplantation and kidney rejection, one of the most common and severe complications. The standard tools used to identify acute rejection largely result in errors and have many drawbacks. In recent years, new and reliable biomarkers have been identified. These methods avoid risks, are noninvasive, and are able to detect rejection even in cases in which acute rejection is clinically asymptomatic and not otherwise identifiable, which is a frequent occurrence. In recent years, several biomarkers have been identified. Very recently, new relevant biomarkers with high positive predictive value and low negative predictive value have been identified. These are the donor-derived cell-free DNA found in the recipient, the gene expression profile of the donor found in the recipient, and the urinary cytokines that are modified in the graft tissue. The aim of this study was to identify the most recent findings in the literature on this topic and to describe the utility and possible limitations of such new biomarkers for kidney rejection.
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, 50139 Florence, Italy
| | - Alberto Rosati
- Division of Nephrology, San Giovanni di Dio Hospital, 50143 Florence, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, 50143 Florence, Italy
| |
Collapse
|
|
21
|
Goutaudier V, Sablik M, Racapé M, Rousseau O, Audry B, Kamar N, Raynaud M, Aubert O, Charreau B, Papuchon E, Danger R, Letertre L, Couzi L, Morelon E, Le Quintrec M, Taupin JL, Vicaut E, Legendre C, Le Mai H, Potluri V, Nguyen TVH, Azoury ME, Pinheiro A, Nouadje G, Sonigo P, Anglicheau D, Tieken I, Vogelaar S, Jacquelinet C, Reese P, Gourraud PA, Brouard S, Lefaucheur C, Loupy A. Design, cohort profile and comparison of the KTD-Innov study: a prospective multidimensional biomarker validation study in kidney allograft rejection. Eur J Epidemiol 2024; 39:549-564. [PMID: 38625480 DOI: 10.1007/s10654-024-01112-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/04/2024] [Indexed: 04/17/2024]
Abstract
There is an unmet need for robust and clinically validated biomarkers of kidney allograft rejection. Here we present the KTD-Innov study (ClinicalTrials.gov, NCT03582436), an unselected deeply phenotyped cohort of kidney transplant recipients with a holistic approach to validate the clinical utility of precision diagnostic biomarkers. In 2018-2019, we prospectively enrolled consecutive adult patients who received a kidney allograft at seven French centers and followed them for a year. We performed multimodal phenotyping at follow-up visits, by collecting clinical, biological, immunological, and histological parameters, and analyzing a panel of 147 blood, urinary and kidney tissue biomarkers. The primary outcome was allograft rejection, assessed at each visit according to the international Banff 2019 classification. We evaluated the representativeness of participants by comparing them with patients from French, European, and American transplant programs transplanted during the same period. A total of 733 kidney transplant recipients (64.1% male and 35.9% female) were included during the study. The median follow-up after transplantation was 12.3 months (interquartile range, 11.9-13.1 months). The cumulative incidence of rejection was 9.7% at one year post-transplant. We developed a distributed and secured data repository in compliance with the general data protection regulation. We established a multimodal biomarker biobank of 16,736 samples, including 9331 blood, 4425 urinary and 2980 kidney tissue samples, managed and secured in a collaborative network involving 7 clinical centers, 4 analytical platforms and 2 industrial partners. Patients' characteristics, immune profiles and treatments closely resembled those of 41,238 French, European and American kidney transplant recipients. The KTD-Innov study is a unique holistic and multidimensional biomarker validation cohort of kidney transplant recipients representative of the real-world transplant population. Future findings from this cohort are likely to be robust and generalizable.
Collapse
Affiliation(s)
- Valentin Goutaudier
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Marta Sablik
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
| | - Maud Racapé
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
| | - Olivia Rousseau
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
- Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des Données, INSERM, CIC 1413, Nantes Université, CHU Nantes, 44000, Nantes, France
| | - Benoit Audry
- Agence de la Biomédecine, Saint Denis la Plaine, France
| | - Nassim Kamar
- Department of Nephrology-Dialysis-Transplantation, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Marc Raynaud
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
| | - Olivier Aubert
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Béatrice Charreau
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Emmanuelle Papuchon
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Richard Danger
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Laurence Letertre
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France
| | - Emmanuel Morelon
- Department of Transplantation, Edouard Herriot University Hospital, Hospices Civils de Lyon, University Lyon, University of Lyon I, Lyon, France
| | - Moglie Le Quintrec
- Department of Nephrology, Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Jean-Luc Taupin
- Immunology and Histocompatibility Laboratory, Medical Biology Department, Saint-Louis Hospital, Paris, France
| | - Eric Vicaut
- Clinical Trial Unit Hospital, Lariboisière Saint-Louis AP-HP, Paris Cité University, Paris, France
| | - Christophe Legendre
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Hoa Le Mai
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Vishnu Potluri
- Department of Biostatistics, Epidemiology and Bioinformatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thi-Van-Ha Nguyen
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | | | | | | | | | - Dany Anglicheau
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Université Paris Cité, Inserm U1151, Necker Enfants-Malades Institute, Paris, France
| | - Ineke Tieken
- Eurotransplant International Foundation, Leiden, the Netherlands
| | - Serge Vogelaar
- Eurotransplant International Foundation, Leiden, the Netherlands
| | | | - Peter Reese
- Department of Biostatistics, Epidemiology and Bioinformatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Pierre-Antoine Gourraud
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
- Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des Données, INSERM, CIC 1413, Nantes Université, CHU Nantes, 44000, Nantes, France
| | - Sophie Brouard
- INSERM UMR 1064, Center for Research in Transplantation and Translational Immunology, ITUN, Nantes Université, CHU Nantes, Nantes, France
| | - Carmen Lefaucheur
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Paris Institute for Transplantation and Organ Regeneration (PITOR), INSERM U970, Université Paris Cité, 56 rue Leblanc, 75015, Paris, France.
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
| |
Collapse
|
|
22
|
Barrett-Chan E, Wang L, Bone J, Thachil A, Vytlingam K, Blydt-Hansen T. Optimizing the approach to monitoring allograft inflammation using serial urinary CXCL10/creatinine testing in pediatric kidney transplant recipients. Pediatr Transplant 2024; 28:e14718. [PMID: 38553815 DOI: 10.1111/petr.14718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/04/2024] [Accepted: 02/05/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. METHODS Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. RESULTS Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. CONCLUSIONS Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.
Collapse
Affiliation(s)
| | - Li Wang
- University of British Columbia, Vancouver, British Columbia, Canada
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Jeffrey Bone
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Amy Thachil
- University of British Columbia, Vancouver, British Columbia, Canada
| | - Kevin Vytlingam
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Tom Blydt-Hansen
- University of British Columbia, Vancouver, British Columbia, Canada
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| |
Collapse
|
|
23
|
Van Loon E, Tinel C, de Loor H, Bossuyt X, Callemeyn J, Coemans M, De Vusser K, Sauvaget V, Olivre J, Koshy P, Kuypers D, Sprangers B, Van Craenenbroeck AH, Vaulet T, Anglicheau D, Naesens M. Automated Urinary Chemokine Assays for Noninvasive Detection of Kidney Transplant Rejection: A Prospective Cohort Study. Am J Kidney Dis 2024; 83:467-476. [PMID: 37777058 DOI: 10.1053/j.ajkd.2023.07.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 07/24/2023] [Accepted: 07/29/2023] [Indexed: 10/02/2023]
Abstract
RATIONALE & OBJECTIVE Prior studies have demonstrated the diagnostic potential of urinary chemokines C-X-C motif ligand 9 (CXCL9) and CXCL10 for kidney transplant rejection. However, their benefit in addition to clinical information has not been demonstrated. We evaluated the diagnostic performance for detecting acute rejection of urinary CXCL9 and CXCL10 when integrated with clinical information. STUDY DESIGN Single-center prospective cohort study. SETTING & PARTICIPANTS We analyzed 1,559 biopsy-paired urinary samples from 622 kidney transplants performed between April 2013 and July 2019 at a single transplant center in Belgium. External validation was performed in 986 biopsy-paired urinary samples. TESTS COMPARED We quantified urinary CXCL9 (uCXCL9) and CXCL10 (uCXCL10) using an automated immunoassay platform and normalized the values to urinary creatinine. Urinary chemokines were incorporated into a multivariable model with routine clinical markers (estimated glomerular filtration rate, donor-specific antibodies, and polyoma viremia) (integrated model). This model was then compared with the tissue diagnosis according to the Banff classification for acute rejection. OUTCOME Acute rejection detected on kidney biopsy using the Banff classification. RESULTS Chemokines integrated with routine clinical markers had high diagnostic value for detection of acute rejection (n=150) (receiver operating characteristic area under the curve 81.3% [95% CI, 77.6-85.0]). The integrated model would help avoid 59 protocol biopsies per 100 patients when the risk for rejection is predicted to be below 10%. The performance of the integrated model was similar in the external validation cohort. LIMITATIONS The cross-sectional nature obviates investigating the evolution over time and prediction of future rejection. CONCLUSIONS The use of an integrated model of urinary chemokines and clinical markers for noninvasive monitoring of rejection could enable a reduction in the number of biopsies. Urinary chemokines may be useful noninvasive biomarkers whose use should be further studied in prospective randomized trials to clarify their role in guiding clinical care and the use of biopsies to detect rejection after kidney transplantation. PLAIN-LANGUAGE SUMMARY Urinary chemokines CXCL9 and CXCL10 have been suggested to be good noninvasive biomarkers of kidney transplant rejection. However, defining a context of use and integration with clinical information is necessary before clinical implementation can begin. In this study, we demonstrated that urinary chemokines CXCL9 and CXCL10, together with clinical information, have substantial diagnostic accuracy for the detection of acute kidney transplant rejection. Application of urinary chemokines together with clinical information may guide biopsy practices following kidney transplantation and potentially reduce the need for kidney transplant biopsies.
Collapse
Affiliation(s)
- Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven
| | - Henriette de Loor
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven
| | - Xavier Bossuyt
- Clinical and Diagnostic Immunology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven; Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Jasper Callemeyn
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven
| | - Katrien De Vusser
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | | | | | | | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven
| | - Amaryllis H Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Thibaut Vaulet
- ESAT STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, Leuven
| | - Dany Anglicheau
- INSERM U1151, Université de Paris, Paris, France; Department of Nephrology and Kidney Transplantation, RTRS Centaure, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven; Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium.
| |
Collapse
|
|
24
|
Abstract
PURPOSE OF REVIEW Urine CXCL10 is a promising biomarker for posttransplant renal allograft monitoring but is currently not widely used for clinical management. RECENT FINDINGS Large retrospective studies and data from a prospective randomized trial as well as a prospective cohort study demonstrate that low urine CXCL10 levels are associated with a low risk of rejection and can exclude BK polyomavirus replication with high certainty. Urine CXCL10 can either be used as part of a multiparameter based risk assessment tool, or as an individual biomarker taking relevant confounders into account. A novel Luminex-based CXCL10 assay has been validated in a multicenter study, and proved to be robust, reproducible, and accurate. SUMMARY Urine CXCL10 is a well characterized inflammation biomarker, which can be used to guide performance of surveillance biopsies. Wide implementation into clinical practice depends on the availability of inexpensive, thoroughly validated assays with approval from regulatory authorities.
Collapse
Affiliation(s)
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology
- HLA-Diagnostic and lmmunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| |
Collapse
|
|
25
|
Lee I, Kwon SJ, Heeger P, Dordick JS. Ultrasensitive ImmunoMag-CRISPR Lateral Flow Assay for Point-of-Care Testing of Urinary Biomarkers. ACS Sens 2024; 9:92-100. [PMID: 38141036 PMCID: PMC11090086 DOI: 10.1021/acssensors.3c01694] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2023]
Abstract
Rapid, accurate, and noninvasive detection of biomarkers in saliva, urine, or nasal fluid is essential for the identification, early diagnosis, and monitoring of cancer, organ failure, transplant rejection, vascular diseases, autoimmune disorders, and infectious diseases. We report the development of an Immuno-CRISPR-based lateral flow assay (LFA) using antibody-DNA barcode complexes with magnetic enrichment of the target urinary biomarkers CXCL9 and CXCL10 for naked eye detection (ImmunoMag-CRISPR LFA). An intermediate approach involving a magnetic bead-based Immuno-CRISPR assay (ImmunoMag-CRISPR) resulted in a limit of detection (LOD) of 0.6 pg/mL for CXCL9. This value surpasses the detection limits achieved by previously reported assays. The highly sensitive detection method was then re-engineered into an LFA format with an LOD of 18 pg/mL for CXCL9, thereby enabling noninvasive early detection of acute kidney transplant rejection. The ImmunoMag-CRISPR LFA was tested on 42 clinical urine samples from kidney transplant recipients, and the assay could determine 11 positive and 31 negative urinary samples through a simple visual comparison of the test line and the control line of the LFA strip. The LFA system was then expanded to quantify the CXCL9 and CXCL10 levels in clinical urine samples from images. This approach has the potential to be extended to a wide range of point-of-care tests for highly sensitive biomarker detection.
Collapse
Affiliation(s)
- Inseon Lee
- Department of Chemical and Biological Engineering, and Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, United States
| | - Seok-Joon Kwon
- Department of Chemical and Biological Engineering, and Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, United States
| | - Peter Heeger
- Comprehensive Transplant Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Jonathan S. Dordick
- Department of Chemical and Biological Engineering, and Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, United States
| |
Collapse
|
|
26
|
Park S, Sellares J, Tinel C, Anglicheau D, Bestard O, Friedewald JJ. European Society of Organ Transplantation Consensus Statement on Testing for Non-Invasive Diagnosis of Kidney Allograft Rejection. Transpl Int 2024; 36:12115. [PMID: 38239762 PMCID: PMC10794444 DOI: 10.3389/ti.2023.12115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/07/2023] [Indexed: 01/22/2024]
Abstract
To address the need for improved biomarkers for kidney transplant rejection, European Society of Organ Transplantation (ESOT) convened a dedicated working group comprised of experts in kidney transplant biomarkers to review literature pertaining to clinical and subclinical acute rejection to develop guidelines in the screening and diagnosis of acute rejection that were subsequently discussed and voted on during the Consensus Conference that took place in person in Prague. The findings and recommendations of the Working Group on Molecular Biomarkers of Kidney Transplant Rejection are presented in this article.
Collapse
Affiliation(s)
- Sookhyeon Park
- Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | | | - Claire Tinel
- Dijon University Hospital, INSERM UMR 1098 Right, UBFC, Dijon, France
| | - Dany Anglicheau
- Necker Hospital, Assistance Publique-Hopitaux de Paris, INSERM U1151, Université Paris-Cité, Paris, France
| | | | - John J. Friedewald
- Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| |
Collapse
|
|
27
|
Venkataraman K, Salehi T, Carroll RP. Immune Checkpoint Inhibitors in Recipients of Renal Allografts. Semin Nephrol 2024; 44:151500. [PMID: 38548484 DOI: 10.1016/j.semnephrol.2024.151500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2024]
Abstract
Kidney transplant recipients are at increased risk of malignancy as a result of immunosuppression and are increasingly exposed to checkpoint inhibitors (CPIs). However, CPI therapy can precipitate allograft rejection. This review aims to summarize the current literature describing the epidemiology, immunological mechanisms, diagnosis, and treatment of CPI-associated allograft rejection.Initial studies of CPIs suggested allograft rejection post commencement of CPIs occured commonly (40-60%), occurring between 2 and 6 weeks after CPI initiation, with a cancer response rate approaching 50%. More recent studies with predefined, structured immunosuppressive regimens have seen rejection rates of 0-12.5%, with rejection occurring later. Allograft biopsy remains the mainstay of diagnosis; however, noninvasive tools are emerging, including donor-derived cell-free DNA, urinary chemokine assessment, and defining alloreactive T-cell clones prior to or during CPI therapy.
Collapse
Affiliation(s)
- Karthik Venkataraman
- Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia
| | - Tania Salehi
- Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia
| | - Robert P Carroll
- Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia; Australian Red Cross Lifeblood Service, Department of Health Sciences, University of South Australia, Adelaide, Australia.
| |
Collapse
|
|
28
|
Rainey A, McKay GJ, English J, Thakkinstian A, Maxwell AP, Corr M. Proteomic analysis investigating kidney transplantation outcomes- a scoping review. BMC Nephrol 2023; 24:346. [PMID: 37993798 PMCID: PMC10666386 DOI: 10.1186/s12882-023-03401-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 11/16/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Kidney transplantation is the optimal treatment option for most patients with end-stage kidney disease given the significantly lower morbidity and mortality rates compared to remaining on dialysis. Rejection and graft failure remain common in transplant recipients with limited improvement in long-term transplant outcomes despite therapeutic advances. There is an unmet need in the development of non-invasive biomarkers that specifically monitor graft function and predict transplant pathologies that affect outcomes. Despite the potential of proteomic investigatory approaches, up to now, no candidate biomarkers of sufficient sensitivity or specificity have translated into clinical use. The aim of this review was to collate and summarise protein findings and protein pathways implicated in the literature to date, and potentially flag putative biomarkers worth validating in independent patient cohorts. METHODS This review followed the Joanna Briggs' Institute Methodology for a scoping review. MedlineALL, Embase, Web of Science Core Collection, Scopus and Google Scholar databases were searched from inception until December 2022. Abstract and full text review were undertaken independently by two reviewers. Data was collated using a pre-designed data extraction tool. RESULTS One hundred one articles met the inclusion criteria. The majority were single-centre retrospective studies of small sample size. Mass spectrometry was the most used technique to evaluate differentially expressed proteins between diagnostic groups and studies identified various candidate biomarkers such as immune or structural proteins. DISCUSSION Putative immune or structural protein candidate biomarkers have been identified using proteomic techniques in multiple sample types including urine, serum and fluid used to perfuse donor kidneys. The most consistent findings implicated proteins associated with tubular dysfunction and immunological regulatory pathways such as leukocyte trafficking. However, clinical translation and adoption of candidate biomarkers is limited, and these will require comprehensive evaluation in larger prospective, multicentre trials.
Collapse
Affiliation(s)
- Anna Rainey
- Centre for Public Health- Queen's University Belfast, Belfast, UK
| | - Gareth J McKay
- Centre for Public Health- Queen's University Belfast, Belfast, UK
| | - Jane English
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Ammarin Thakkinstian
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Michael Corr
- Centre for Public Health- Queen's University Belfast, Belfast, UK.
| |
Collapse
|
|
29
|
Tan HZ, Sprangers B. Proton pump inhibitors and adverse kidney outcomes during immune checkpoint blockade: time to sound the alarm? Clin Kidney J 2023; 16:1709-1713. [PMID: 37915924 PMCID: PMC10616439 DOI: 10.1093/ckj/sfad205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Indexed: 11/03/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have significantly altered the treatment landscape for cancer in the last decade. However, their benefits are often offset by therapy-limiting immune-related adverse events (irAEs). Acute interstitial nephritis (AIN) is the most common renal irAE, but the exact mechanisms underlying its development are poorly understood. ICI-induced immune activation against drug-derived antigens, leading to an inflammatory response within the kidney interstitium, has been postulated, evidenced by current observations of a higher incidence of ICI-associated AIN in patients receiving AIN-inducing drugs such as proton pump inhibitors (PPIs). The role of PPIs in this specific context has garnered significant attention, given their ubiquitous use and sometimes misuse. In this issue of CKJ Miao et al. summarise and synthesize the best available evidence to clarify the interactions of PPIs with ICIs in the development of AIN and other adverse kidney outcomes. The sum of evidence provided appear to implicate PPIs in the development of clinically significant short- and long-term kidney-related adverse effects in patients on immune checkpoint blockade, although causality cannot be proven. In this editorial we discuss the key practical implications of these findings and emphasize the need for further quality studies to delineate the true relationship of ICIs and PPIs in the development of AIN.
Collapse
Affiliation(s)
- Hui Zhuan Tan
- Department of Renal Medicine, Singapore General Hospital, Singapore
| | - Ben Sprangers
- Biomedical Research Institute, Department of Immunology and Infection, UHasselt, Diepenbeek, Belgium
- Department of Nephrology, Ziekenhuis Oost Limburg, Genk, Belgium
| |
Collapse
|
|
30
|
Sun Z, Zhang Z, Banu K, Gibson IW, Colvin RB, Yi Z, Zhang W, De Kumar B, Reghuvaran A, Pell J, Manes TD, Djamali A, Gallon L, O’Connell PJ, He JC, Pober JS, Heeger PS, Menon MC. Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival. J Clin Invest 2023; 133:e170420. [PMID: 37676733 PMCID: PMC10617779 DOI: 10.1172/jci170420] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 09/06/2023] [Indexed: 09/09/2023] Open
Abstract
Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1-dependent effects on T cells.
Collapse
Affiliation(s)
- Zeguo Sun
- Division of Nephrology, Department of Medicine
| | - Zhongyang Zhang
- Department of Genetics and Genomic Science, and
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Khadija Banu
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Ian W. Gibson
- Max Rady college of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Zhengzi Yi
- Division of Nephrology, Department of Medicine
| | | | - Bony De Kumar
- Yale Center for Genomics, New Haven, Connecticut, USA
| | - Anand Reghuvaran
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - John Pell
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas D. Manes
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | | | - Lorenzo Gallon
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Philip J. O’Connell
- The Westmead Institute for Medical Research, University of Sydney, New South Wales, Australia
| | | | - Jordan S. Pober
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | | | - Madhav C. Menon
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| |
Collapse
|
|
31
|
Farkona S, Pastrello C, Konvalinka A. Proteomics: Its Promise and Pitfalls in Shaping Precision Medicine in Solid Organ Transplantation. Transplantation 2023; 107:2126-2142. [PMID: 36808112 DOI: 10.1097/tp.0000000000004539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Solid organ transplantation is an established treatment of choice for end-stage organ failure. However, all transplant patients are at risk of developing complications, including allograft rejection and death. Histological analysis of graft biopsy is still the gold standard for evaluation of allograft injury, but it is an invasive procedure and prone to sampling errors. The past decade has seen an increased number of efforts to develop minimally invasive procedures for monitoring allograft injury. Despite the recent progress, limitations such as the complexity of proteomics-based technology, the lack of standardization, and the heterogeneity of populations that have been included in different studies have hindered proteomic tools from reaching clinical transplantation. This review focuses on the role of proteomics-based platforms in biomarker discovery and validation in solid organ transplantation. We also emphasize the value of biomarkers that provide potential mechanistic insights into the pathophysiology of allograft injury, dysfunction, or rejection. Additionally, we forecast that the growth of publicly available data sets, combined with computational methods that effectively integrate them, will facilitate a generation of more informed hypotheses for potential subsequent evaluation in preclinical and clinical studies. Finally, we illustrate the value of combining data sets through the integration of 2 independent data sets that pinpointed hub proteins in antibody-mediated rejection.
Collapse
Affiliation(s)
- Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada
| |
Collapse
|
|
32
|
Peruzzi L, Deaglio S. Rejection markers in kidney transplantation: do new technologies help children? Pediatr Nephrol 2023; 38:2939-2955. [PMID: 36648536 PMCID: PMC10432336 DOI: 10.1007/s00467-022-05872-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 12/18/2022] [Accepted: 12/19/2022] [Indexed: 01/18/2023]
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.
Collapse
Affiliation(s)
- Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Department, City of Health and Science University Hospital, Piazza Polonia 94, 10126, Turin, Italy.
| | - Silvia Deaglio
- Immunogenetics and Transplant Biology Service, City of Health and Science University Hospital, Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| |
Collapse
|
|
33
|
Novacescu D, Latcu SC, Bardan R, Daminescu L, Cumpanas AA. Contemporary Biomarkers for Renal Transplantation: A Narrative Overview. J Pers Med 2023; 13:1216. [PMID: 37623466 PMCID: PMC10456039 DOI: 10.3390/jpm13081216] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/18/2023] [Accepted: 07/28/2023] [Indexed: 08/26/2023] Open
Abstract
Renal transplantation (RT) is the preferred treatment for end-stage renal disease. However, clinical challenges persist, i.e., early detection of graft dysfunction, timely identification of rejection episodes, personalization of immunosuppressive therapy, and prediction of long-term graft survival. Biomarkers have emerged as valuable tools to address these challenges and revolutionize RT patient care. Our review synthesizes the existing scientific literature to highlight promising biomarkers, their biological characteristics, and their potential roles in enhancing clinical decision-making and patient outcomes. Emerging non-invasive biomarkers seemingly provide valuable insights into the immunopathology of nephron injury and allograft rejection. Moreover, we analyzed biomarkers with intra-nephron specificities, i.e., glomerular vs. tubular (proximal vs. distal), which can localize an injury in different nephron areas. Additionally, this paper provides a comprehensive analysis of the potential clinical applications of biomarkers in the prediction, detection, differential diagnosis and assessment of post-RT non-surgical allograft complications. Lastly, we focus on the pursuit of immune tolerance biomarkers, which aims to reclassify transplant recipients based on immune risk thresholds, guide personalized immunosuppression strategies, and ultimately identify patients for whom immunosuppression may safely be reduced. Further research, validation, standardization, and prospective studies are necessary to fully harness the clinical utility of RT biomarkers and guide the development of targeted therapies.
Collapse
Affiliation(s)
- Dorin Novacescu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Razvan Bardan
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Liviu Daminescu
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
| | - Alin Adrian Cumpanas
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| |
Collapse
|
|
34
|
Moledina DG, Obeid W, Smith RN, Rosales I, Sise ME, Moeckel G, Kashgarian M, Kuperman M, Campbell KN, Lefferts S, Meliambro K, Bitzer M, Perazella MA, Luciano RL, Pober JS, Cantley LG, Colvin RB, Wilson FP, Parikh CR. Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis. J Clin Invest 2023; 133:e168950. [PMID: 37395276 PMCID: PMC10313360 DOI: 10.1172/jci168950] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/14/2023] [Indexed: 07/04/2023] Open
Abstract
BackgroundAcute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.MethodsIn a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.ResultsIn aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10-5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8-20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86-1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10-6).ConclusionWe identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.FundingThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O'Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Collapse
Affiliation(s)
- Dennis G. Moledina
- Section of Nephrology, Department of Internal Medicine and
- Clinical and Translational Research Accelerator, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Wassim Obeid
- Division of Nephrology, Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Rex N. Smith
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
- Immunopathology Research Laboratory and
| | - Ivy Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
- Immunopathology Research Laboratory and
| | - Meghan E. Sise
- Section of Nephrology, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Gilbert Moeckel
- Section of Renal Pathology, Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Michael Kashgarian
- Section of Renal Pathology, Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Kirk N. Campbell
- Division of Nephrology, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sean Lefferts
- Division of Nephrology, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kristin Meliambro
- Division of Nephrology, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Markus Bitzer
- Section of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | - Jordan S. Pober
- Department of Pathology and
- Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
- Immunopathology Research Laboratory and
| | - F. Perry Wilson
- Section of Nephrology, Department of Internal Medicine and
- Clinical and Translational Research Accelerator, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Chirag R. Parikh
- Division of Nephrology, Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
35
|
Ho J, Schaub S, Jackson AM, Balshaw R, Carroll R, Cun S, De Serres SA, Fantus D, Handschin J, Hönger G, Jevnikar AM, Kleiser M, Lee JH, Li Y, Nickerson P, Pei R, Pochinco D, Shih R, Trinh M, Wang J, Nguyen J, Knechtle S. Multicenter Validation of a Urine CXCL10 Assay for Noninvasive Monitoring of Renal Transplants. Transplantation 2023; 107:1630-1641. [PMID: 36949034 DOI: 10.1097/tp.0000000000004554] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
BACKGROUND Urine CXCL10 (C-X-C motif chemokine ligand 10, interferon gamma-induced protein 10 [IP10]) outperforms standard-of-care monitoring for detecting subclinical and early clinical T-cell-mediated rejection (TCMR) and may advance TCMR therapy development through biomarker-enriched trials. The goal was to perform an international multicenter validation of a CXCL10 bead-based immunoassay (Luminex) for transplant surveillance and compare with an electrochemiluminescence-based (Meso Scale Discovery [MSD]) assay used in transplant trials. METHODS Four laboratories participated in the Luminex assay development and evaluation. Urine CXCL10 was measured by Luminex and MSD in 2 independent adult kidney transplant trial cohorts (Basel and TMCT04). In an independent test and validation set, a linear mixed-effects model to predict (log 10 -transformed) MSD CXCL10 from Luminex CXCL10 was developed to determine the conversion between assays. Net reclassification was determined after mathematical conversion. RESULTS The Luminex assay was precise, with an intra- and interassay coefficient of variation 8.1% and 9.3%; showed modest agreement between 4 laboratories (R 0.96 to 0.99, P < 0.001); and correlated with known CXCL10 in a single- (n = 100 urines, R 0.94 to 0.98, P < 0.001) and multicenter cohort (n = 468 urines, R 0.92, P < 0.001) but the 2 assays were not equivalent by Passing-Bablok regression. Linear mixed-effects modeling demonstrated an intercept of -0.490 and coefficient of 1.028, showing Luminex CXCL10 are slightly higher than MSD CXCL10, but the agreement is close to 1.0. After conversion of the biopsy thresholds, the decision to biopsy would be changed for only 6% (5/85) patients showing acceptable reclassification. CONCLUSIONS These data demonstrate this urine CXCL10 Luminex immunoassay is robust, reproducible, and accurate, indicating it can be readily translated into clinical HLA laboratories for serial posttransplant surveillance.
Collapse
Affiliation(s)
- Julie Ho
- Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, Canada
- Transplant Manitoba, Shared Health Manitoba, Winnipeg, Canada
| | - Stefan Schaub
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | | | - Robert Balshaw
- George and Fay Yee Center for Healthcare Innovation, Manitoba, Canada
| | - Robert Carroll
- Royal Adelaide Hospital, University of Adelaide, SA, Australia
| | - Sylvia Cun
- Thermo Fisher Scientific, Los Angeles, CA
| | | | - Daniel Fantus
- Division of Nephrology, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM) and Centre de Recherche du CHUM (CRCHUM), Montréal, Québec, Canada
| | - Joelle Handschin
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gideon Hönger
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Anthony M Jevnikar
- Department of Medicine, Western University and Multiorgan Transplant Program, London, ON, Canada
| | - Marc Kleiser
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | | | - Yan Li
- Department of Surgery and Immunology, Duke University, Durham, NC
| | - Peter Nickerson
- Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, Canada
- Transplant Manitoba, Shared Health Manitoba, Winnipeg, Canada
- Canadian Blood Services HLA Laboratory, Diagnostic Services of Manitoba, Canada
| | - Rui Pei
- Thermo Fisher Scientific, Los Angeles, CA
| | - Denise Pochinco
- Canadian Blood Services HLA Laboratory, Diagnostic Services of Manitoba, Canada
| | - Remi Shih
- Terasaki Innovation Center, Los Angeles, CA
| | | | - Jason Wang
- Thermo Fisher Scientific, Los Angeles, CA
| | | | - Stuart Knechtle
- Department of Surgery and Immunology, Duke University, Durham, NC
| |
Collapse
|
|
36
|
Harada H, Fukuzawa N, Abe T, Imamura R, Masaki N, Fujiyama N, Sato S, Hatakeyama S, Nishimura K, Kishikawa H, Iwami D, Hotta K, Miura M, Ide K, Nakamura M, Kosoku A, Uchida J, Murakami T, Tsuji T. Development and nationwide validation of kidney graft injury markers using urinary exosomes and microvesicles (complete English translation of the Japanese version). BMC Nephrol 2023; 24:158. [PMID: 37280521 DOI: 10.1186/s12882-023-03189-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 04/27/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Non-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients. METHODS One hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses. RESULTS EV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850). CONCLUSIONS KGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy.
Collapse
Affiliation(s)
- Hiroshi Harada
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, 1-1 Kita 11-jo Nishi 13-chome, Chuou- ku, Sapporo, Hokkaido, 060-8604, Japan.
- Harada Urological Clinic, 4F Hokuyaku Bldg., 1-1 Kita 11-jo Nishi 14-chome, Chuou-ku, Sapporo, Hokkaido, 060-0011, Japan.
| | - Nobuyuki Fukuzawa
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, 1-1 Kita 11-jo Nishi 13-chome, Chuou- ku, Sapporo, Hokkaido, 060-8604, Japan
| | - Toyofumi Abe
- Department of Urology, Graduate School of Medicine, Faculty of Medicine, Osaka University, 1 Machikaneyama- cho, Toyonaka, Osaka, 560-0043, Japan
| | - Ryoichi Imamura
- Department of Urology, Graduate School of Medicine, Faculty of Medicine, Osaka University, 1 Machikaneyama- cho, Toyonaka, Osaka, 560-0043, Japan
| | - Noriyuki Masaki
- Department of Kidney Surgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162- 8666, Japan
| | - Nobuhiro Fujiyama
- Department of Center for Kidney Disease and Transplantation, Akita University Hospital, 44-2 Hiroomote Azahasunuma, Akita, Akita, 010-8543, Japan
| | - Shigeru Sato
- Department of Center for Kidney Disease and Transplantation, Akita University Hospital, 44-2 Hiroomote Azahasunuma, Akita, Akita, 010-8543, Japan
| | - Shingo Hatakeyama
- Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Kenji Nishimura
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanji-cho, Nishinomiya, Hyogo, Japan
| | - Hidefumi Kishikawa
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanji-cho, Nishinomiya, Hyogo, Japan
| | - Daiki Iwami
- Division of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Kiyohiko Hotta
- Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Kita 15-jo Nishi 7-chome, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masayoshi Miura
- Department of Kidney Transplant Surgery, Sapporo Hokuyu Hospital, 5-1 Higashi-sapporo 6-jo 6-chome, Shiroishi- ku, Sapporo, Hokkaido, 003-0006, Japan
| | - Kentaro Ide
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biochemical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Michio Nakamura
- Department of Transplant Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
| | - Akihiro Kosoku
- Department of Urology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-Machi, Abeno-ku, Osaka, Osaka, 545- 8585, Japan
| | - Junji Uchida
- Department of Urology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-Machi, Abeno-ku, Osaka, Osaka, 545- 8585, Japan
| | - Taku Murakami
- R&D Center, Hitachi Chemical Co. America, Ltd. 1003 Health Sciences Road, Irvine, CA, 92617, USA
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, 1-1 Kita 11-jo Nishi 13-chome, Chuou-ku, Sapporo, Hokkaido, 060-8604, Japan
| |
Collapse
|
|
37
|
Yao Q, Wang C, Wang Y, Xiang W, Chen Y, Zhou Q, Chen J, Jiang H, Chen D. STXBP3 and GOT2 predict immunological activity in acute allograft rejection. Front Immunol 2022; 13:1025681. [PMID: 36532048 PMCID: PMC9751189 DOI: 10.3389/fimmu.2022.1025681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/18/2022] [Indexed: 12/04/2022] Open
Abstract
Background Acute allograft rejection (AR) following renal transplantation contributes to chronic rejection and allograft dysfunction. The current diagnosis of AR remains dependent on renal allograft biopsy which cannot immediately detect renal allograft injury in the presence of AR. In this study, sensitive biomarkers for AR diagnosis were investigated and developed to protect renal function. Methods We analyzed pre- and postoperative data from five databases combined with our own data to identify the key differently expressed genes (DEGs). Furthermore, we performed a bioinformatics analysis to determine the immune characteristics of DEGs. The expression of key DEGs was further confirmed using the real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemical (IHC) staining in patients with AR. ROC curves analysis was used to estimate the performance of key DEGs in the early diagnosis of AR. Results We identified glutamic-oxaloacetic transaminase 2 (GOT2) and syntaxin binding protein 3 (STXBP3) as key DEGs. The higher expression of STXBP3 and GOT2 in patients with AR was confirmed using RT-qPCR, ELISA, and IHC staining. ROC curve analysis also showed favorable values of STXBP3 and GOT2 for the diagnosis of early stage AR. Conclusions STXBP3 and GOT2 could reflect the immunological status of patients with AR and have strong potential for the diagnosis of early-stage AR.
Collapse
Affiliation(s)
- Qinfan Yao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Cuili Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Yucheng Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Wenyu Xiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Yin Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Qin Zhou
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Hong Jiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China,*Correspondence: Dajin Chen, ; Hong Jiang,
| | - Dajin Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China,Institute of Nephropathy, Zhejiang University, Hangzhou, China,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China,*Correspondence: Dajin Chen, ; Hong Jiang,
| |
Collapse
|
|
38
|
Yamagishi A, Nishida H, Ito H, Fukuhara H, Tsuchiya N. Urinary dipeptidyl peptidase-4 is a useful marker for tubulitis, and it is released from the tubular cells of kidney transplant recipients. RENAL REPLACEMENT THERAPY 2022. [DOI: 10.1186/s41100-022-00421-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Biomarkers are needed to diagnose kidney rejection in transplant recipients. We evaluated whether dipeptidyl peptidase-4 (DPP-4) could serve as a biomarker of rejection.
Methods
We determined DPP-4 concentrations and enzymatic activities in serum and urine, as well as DPP-4 expression in 49 kidney biopsy samples from 28 kidney transplant recipients. This study was approved by the ethical standards of the institutional research committee and comply with Helsinki declaration. All patients provided their informed consent. Donors were not from prisoners and were not paid or coerced.
Results
Serum and urinary DPP-4 activities closely correlated with DPP-4 concentrations, but were suppressed by DPP-4 inhibitors. Urinary DPP-4 concentrations increased with acute T cell-mediated rejection (ATCMR; p = 0.030) and higher Banff t and i scores (p < 0.001), and correlated with urinary protein/creatinine ratios (r = 0.450), and inversely with estimated glomerular filtration rate (r = − 0.604). The area under the receiver operator characteristics curves for urinary DPP-4 concentrations with either Banff t3 or i3 scores were 0.811 (95% confidence interval: 0.687–0.934). The expression of DPP-4 in renal tubular cells was decreased in patients with ATCMR and higher in those with Banff t, i, ct, ci, ah, and ti scores, but was not associated with interstitial fibrosis/tubular atrophy.
Conclusions
We speculated that ATCMR leads to DPP-4 release from tubular cells into urine, resulting in a decrease in tubular cell expression. If so, then ATCMR would induce the elevation of urinary DPP-4 and could therefore serve as a biomarker of tubulitis.
Collapse
|
|
39
|
Anwar IJ, Srinivas TR, Gao Q, Knechtle SJ. Shifting Clinical Trial Endpoints in Kidney Transplantation: The Rise of Composite Endpoints and Machine Learning to Refine Prognostication. Transplantation 2022; 106:1558-1564. [PMID: 35323161 PMCID: PMC10900533 DOI: 10.1097/tp.0000000000004107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The measurement of outcomes in kidney transplantation has been more accurately documented than almost any other surgical procedure result in recent decades. With significant improvements in short- and long-term outcomes related to optimized immunosuppression, outcomes have gradually shifted away from conventional clinical endpoints (ie, patient and graft survival) to surrogate and composite endpoints. This article reviews how outcomes measurements have evolved in the past 2 decades in the setting of increased data collection and summarizes recent advances in outcomes measurements pertaining to clinical, histopathological, and immune outcomes. Finally, we discuss the use of composite endpoints and Bayesian concepts, specifically focusing on the integrative box risk prediction score, in conjunction with machine learning to refine prognostication.
Collapse
Affiliation(s)
- Imran J Anwar
- Department of Surgery, Duke Transplant Center, Duke University School of Medicine, Durham, NC
| | | | - Qimeng Gao
- Department of Surgery, Duke Transplant Center, Duke University School of Medicine, Durham, NC
| | - Stuart J Knechtle
- Department of Surgery, Duke Transplant Center, Duke University School of Medicine, Durham, NC
| |
Collapse
|
|
40
|
Grothgar E, Goerlich N, Samans B, Skopnik CM, Metzke D, Klocke J, Prskalo L, Freund P, Wagner L, Duerr M, Matz M, Olek S, Budde K, Paliege A, Enghard P. Urinary CD8+HLA-DR+ T Cell Abundance Non-invasively Predicts Kidney Transplant Rejection. Front Med (Lausanne) 2022; 9:928516. [PMID: 35911418 PMCID: PMC9334669 DOI: 10.3389/fmed.2022.928516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/23/2022] [Indexed: 12/05/2022] Open
Abstract
Early detection of kidney transplant (KT) rejection remains a challenge in patient care. Non-invasive biomarkers hold high potential to detect rejection, adjust immunosuppression, and monitor KT patients. So far, no approach has fully satisfied requirements to innovate routine monitoring of KT patients. In this two-center study we analyzed a total of 380 urine samples. T cells and tubular epithelial cells were quantified in KT patients with graft deterioration using flow cytometry. Epigenetic urine cell quantification was used to confirm flow cytometric results. Moreover, a cohort of KT patients was followed up during the first year after transplantation, tracking cell subsets over time. Abundance of urinary cell counts differed in patients with and without rejection. Most strikingly, various T cell subsets were enriched in patients with T cell-mediated rejection (TCMR) compared to patients without TCMR. Among T cell subsets, CD8+HLA-DR+ T cells were most distinctive (AUC = 0.91, Spec.: 95.9%, Sens.: 76.5%). Epigenetic analysis confirmed T cell and tubular epithelial cell quantities as determined by flow cytometry. Urinary T cell abundance in new KT patients decreased during their first year after transplantation. In conclusion urinary T cells reflect intrarenal inflammation in TCMR. T cell subsets yield high potential to monitor KT patients and detect rejection. Hereby we present a promising biomarker to non-invasively diagnose TCMR.
Collapse
Affiliation(s)
- Emil Grothgar
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Nina Goerlich
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Bjoern Samans
- Ivana Türbachova Laboratory for Epigenetics, Precision for Medicine GmbH, Berlin, Germany
| | - Christopher M. Skopnik
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Diana Metzke
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Jan Klocke
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Luka Prskalo
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Paul Freund
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Leonie Wagner
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Michael Duerr
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mareen Matz
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Sven Olek
- Ivana Türbachova Laboratory for Epigenetics, Precision for Medicine GmbH, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Philipp Enghard
- Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| |
Collapse
|
|
41
|
Proteomics for Biomarker Discovery for Diagnosis and Prognosis of Kidney Transplantation Rejection. Proteomes 2022; 10:proteomes10030024. [PMID: 35893765 PMCID: PMC9326686 DOI: 10.3390/proteomes10030024] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 02/07/2023] Open
Abstract
Renal transplantation is currently the treatment of choice for end-stage kidney disease, enabling a quality of life superior to dialysis. Despite this, all transplanted patients are at risk of allograft rejection processes. The gold-standard diagnosis of graft rejection, based on histological analysis of kidney biopsy, is prone to sampling errors and carries high costs and risks associated with such invasive procedures. Furthermore, the routine clinical monitoring, based on urine volume, proteinuria, and serum creatinine, usually only detects alterations after graft histologic damage and does not differentiate between the diverse etiologies. Therefore, there is an urgent need for new biomarkers enabling to predict, with high sensitivity and specificity, the rejection processes and the underlying mechanisms obtained from minimally invasive procedures to be implemented in routine clinical surveillance. These new biomarkers should also detect the rejection processes as early as possible, ideally before the 78 clinical outputs, while enabling balanced immunotherapy in order to minimize rejections and reducing the high toxicities associated with these drugs. Proteomics of biofluids, collected through non-invasive or minimally invasive analysis, e.g., blood or urine, present inherent characteristics that may provide biomarker candidates. The current manuscript reviews biofluids proteomics toward biomarkers discovery that specifically identify subclinical, acute, and chronic immune rejection processes while allowing for the discrimination between cell-mediated or antibody-mediated processes. In time, these biomarkers will lead to patient risk stratification, monitoring, and personalized and more efficient immunotherapies toward higher graft survival and patient quality of life.
Collapse
|
|
42
|
Budhiraja P, Heilman RL, Edwards AS, Kaplan B. The Problem With Predicting Uncommon Events: The Critical Effect of Prevalence in Test Performance. Transplant Proc 2022; 54:1742-1744. [DOI: 10.1016/j.transproceed.2022.03.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/26/2022] [Indexed: 10/16/2022]
|
|
43
|
Van Loon E, Lamarthée B, Barba T, Claes S, Coemans M, de Loor H, Emonds MP, Koshy P, Kuypers D, Proost P, Senev A, Sprangers B, Tinel C, Thaunat O, Van Craenenbroeck AH, Schols D, Naesens M. Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings. Front Immunol 2022; 13:818569. [PMID: 35281018 PMCID: PMC8904423 DOI: 10.3389/fimmu.2022.818569] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/10/2022] [Indexed: 12/17/2022] Open
Abstract
Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation.
Collapse
Affiliation(s)
- Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Thomas Barba
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Sandra Claes
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Leuven Biostatistics and Statistical Bioinformatics Centre, Department of Public Health and Primary Care, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Henriette de Loor
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Marie-Paule Emonds
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Priyanka Koshy
- Department of Imaging and Pathology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Amaryllis H Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dominique Schols
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
44
|
Borges TJ, Abarzua P, Gassen RB, Kollar B, Lima-Filho M, Aoyama BT, Gluhova D, Clark RA, Islam SA, Pomahac B, Murphy GF, Lian CG, Talbot SG, Riella LV. T cell-attracting CCL18 chemokine is a dominant rejection signal during limb transplantation. Cell Rep Med 2022; 3:100559. [PMID: 35492875 PMCID: PMC9040185 DOI: 10.1016/j.xcrm.2022.100559] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 01/14/2022] [Accepted: 02/12/2022] [Indexed: 11/16/2022]
Abstract
Limb transplantation is a life-changing procedure for amputees. However, limb recipients have a 6-fold greater rejection rate than solid organ transplant recipients, related in part to greater immunogenicity of the skin. Here, we report a detailed immunological and molecular characterization of individuals who underwent bilateral limb transplantation at our institution. Circulating Th17 cells are increased in limb transplant recipients over time. Molecular characterization of 770 genes in skin biopsies reveals upregulation of T cell effector immune molecules and chemokines, particularly CCL18. Skin antigen-presenting cells primarily express the chemokine CCL18, which binds to the CCR8 receptor. CCL18 treatment recruits more allo-T cells to the skin xenograft in a humanized skin transplantation model, leading to signs of accelerated graft rejection. Blockade of CCR8 remarkedly decreases CCL18-induced allo-T cell infiltration. Our results suggest that targeting the CCL18:CCR8 pathway could be a promising immunosuppressive approach in transplantation.
Collapse
Affiliation(s)
- Thiago J. Borges
- Schuster Family Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
| | - Phammela Abarzua
- Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Rodrigo B. Gassen
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
| | - Branislav Kollar
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, University of Freiburg Faculty of Medicine, 79106 Freiburg, Germany
| | - Mauricio Lima-Filho
- Schuster Family Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Bruno T. Aoyama
- Schuster Family Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Diana Gluhova
- DF/HCC Specialized Histopathology Core – Massachusetts General Hospital Site, Boston, MA 02129, USA
| | - Rachael A. Clark
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston MA 02115, USA
| | - Sabina A. Islam
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
| | - Bohdan Pomahac
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - George F. Murphy
- Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Christine G. Lian
- Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Simon G. Talbot
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Leonardo V. Riella
- Schuster Family Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| |
Collapse
|
|
45
|
Al Jurdi A, Gassen RB, Borges TJ, Solhjou Z, Hullekes FE, Lape IT, Efe O, Alghamdi A, Patel P, Choi JY, Mohammed MT, Bohan B, Pattanayak V, Rosales I, Cravedi P, Kotton CN, Azzi JR, Riella LV. Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination. Front Immunol 2022; 13:838985. [PMID: 35281011 PMCID: PMC8913529 DOI: 10.3389/fimmu.2022.838985] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 02/08/2022] [Indexed: 01/14/2023] Open
Abstract
Introduction Studies have shown reduced antiviral responses in kidney transplant recipients (KTRs) following SARS-CoV-2 mRNA vaccination, but data on post-vaccination alloimmune responses and antiviral responses against the Delta (B.1.617.2) variant are limited. Materials and methods To address this issue, we conducted a prospective, multi-center study of 58 adult KTRs receiving mRNA-BNT162b2 or mRNA-1273 vaccines. We used multiple complementary non-invasive biomarkers for rejection monitoring including serum creatinine, proteinuria, donor-derived cell-free DNA, peripheral blood gene expression profile (PBGEP), urinary CXCL9 mRNA and de novo donor-specific antibodies (DSA). Secondary outcomes included development of anti-viral immune responses against the wild-type and Delta variant of SARS-CoV-2. Results At a median of 85 days, no KTRs developed de novo DSAs and only one patient developed acute rejection following recent conversion to belatacept, which was associated with increased creatinine and urinary CXCL9 levels. During follow-up, there were no significant changes in proteinuria, donor-derived cell-free DNA levels or PBGEP. 36% of KTRs in our cohort developed anti-wild-type spike antibodies, 75% and 55% of whom had neutralizing responses against wild-type and Delta variants respectively. A cellular response against wild-type S1, measured by interferon-γ-ELISpot assay, developed in 38% of KTRs. Cellular responses did not differ in KTRs with or without antibody responses. Conclusions SARS-CoV-2 mRNA vaccination in KTRs did not elicit a significant alloimmune response. About half of KTRs who develop anti-wild-type spike antibodies after two mRNA vaccine doses have neutralizing responses against the Delta variant. There was no association between anti-viral humoral and cellular responses.
Collapse
Affiliation(s)
- Ayman Al Jurdi
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Rodrigo B. Gassen
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Thiago J. Borges
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Zhabiz Solhjou
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MA, United States
| | - Frank E. Hullekes
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Isadora T. Lape
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Orhan Efe
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Areej Alghamdi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MA, United States
| | - Poojan Patel
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MA, United States
| | - John Y. Choi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MA, United States
| | - Mostafa T. Mohammed
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MA, United States
- Clinical Pathology Department, Minia University, Minya, Egypt
| | - Brigid Bohan
- Histocompatibility Laboratory, Massachusetts General Hospital, Boston, MA, United States
| | - Vikram Pattanayak
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Ivy Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Camille N. Kotton
- Transplant and Immunocompromised Host Infectious Diseases Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Jamil R. Azzi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Boston, MA, United States
| | - Leonardo V. Riella
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| |
Collapse
|
|
46
|
Westphal SG, Mannon RB. Emerging biomarkers in kidney transplantation and challenge of clinical implementation. Curr Opin Organ Transplant 2022; 27:15-21. [PMID: 34939960 DOI: 10.1097/mot.0000000000000941] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Despite improvement in short-term outcomes after kidney transplantation, long-term outcomes remain suboptimal. Conventional biomarkers are limited in their ability to reliably identify early immunologic and nonimmunologic injury. Novel biomarkers are needed for noninvasive diagnosis of subclinical injury, prediction of response to treatment, and personalization of the care of kidney transplant recipients. RECENT FINDINGS Recent biotechnological advances have led to the discovery of promising molecular biomarker candidates. However, translating potential biomarkers from bench to clinic is challenging, and many potential biomarkers are abandoned prior to clinical implementation. Despite these challenges, several promising urine, blood, and tissue novel molecular biomarkers have emerged and are approaching incorporation into clinical practice. SUMMARY This article highlights the challenges in adopting biomarker-driven posttransplant management and reviews several promising emerging novel biomarkers that are approaching clinical implementation.
Collapse
Affiliation(s)
- Scott G Westphal
- Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | | |
Collapse
|
|
47
|
Seiler LK, Phung NL, Nikolin C, Immenschuh S, Erck C, Kaufeld J, Haller H, Falk CS, Jonczyk R, Lindner P, Thoms S, Siegl J, Mayer G, Feederle R, Blume CA. An Antibody-Aptamer-Hybrid Lateral Flow Assay for Detection of CXCL9 in Antibody-Mediated Rejection after Kidney Transplantation. Diagnostics (Basel) 2022; 12:diagnostics12020308. [PMID: 35204399 PMCID: PMC8871475 DOI: 10.3390/diagnostics12020308] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
Chronic antibody-mediated rejection (AMR) is a key limiting factor for the clinical outcome of a kidney transplantation (Ktx), where early diagnosis and therapeutic intervention is needed. This study describes the identification of the biomarker CXC-motif chemokine ligand (CXCL) 9 as an indicator for AMR and presents a new aptamer-antibody-hybrid lateral flow assay (hybrid-LFA) for detection in urine. Biomarker evaluation included two independent cohorts of kidney transplant recipients (KTRs) from a protocol biopsy program and used subgroup comparisons according to BANFF-classifications. Plasma, urine and biopsy lysate samples were analyzed with a Luminex-based multiplex assay. The CXCL9-specific hybrid-LFA was developed based upon a specific rat antibody immobilized on a nitrocellulose-membrane and the coupling of a CXCL9-binding aptamer to gold nanoparticles. LFA performance was assessed according to receiver operating characteristic (ROC) analysis. Among 15 high-scored biomarkers according to a neural network analysis, significantly higher levels of CXCL9 were found in plasma and urine and biopsy lysates of KTRs with biopsy-proven AMR. The newly developed hybrid-LFA reached a sensitivity and specificity of 71% and an AUC of 0.79 for CXCL9. This point-of-care-test (POCT) improves early diagnosis-making in AMR after Ktx, especially in KTRs with undetermined status of donor-specific HLA-antibodies.
Collapse
Affiliation(s)
- Lisa K. Seiler
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Ngoc Linh Phung
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Christoph Nikolin
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany; (C.N.); (S.I.)
| | - Stephan Immenschuh
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany; (C.N.); (S.I.)
| | - Christian Erck
- Helmholtz Centre for Infection Research, Cellular Proteome Research Group, 38124 Braunschweig, Germany;
| | - Jessica Kaufeld
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (J.K.); (H.H.)
| | - Hermann Haller
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (J.K.); (H.H.)
| | - Christine S. Falk
- Institute for Transplant Immunology, Hannover Medical School, 30625 Hannover, Germany;
| | - Rebecca Jonczyk
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Patrick Lindner
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Stefanie Thoms
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
| | - Julia Siegl
- Chemical Biology & Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53121 Bonn, Germany; (J.S.); (G.M.)
- Center of Aptamer Research & Development (CARD), University of Bonn, 53121 Bonn, Germany
| | - Günter Mayer
- Chemical Biology & Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53121 Bonn, Germany; (J.S.); (G.M.)
- Center of Aptamer Research & Development (CARD), University of Bonn, 53121 Bonn, Germany
| | - Regina Feederle
- Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz-Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;
| | - Cornelia A. Blume
- Institute of Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (L.K.S.); (N.L.P.); (R.J.); (P.L.); (S.T.)
- Correspondence:
| |
Collapse
|
|
48
|
Xiang W, Han S, Wang C, Chen H, Shen L, Zhu T, Wang K, Wei W, Qin J, Shushakova N, Rong S, Haller H, Jiang H, Chen J. Pre-transplant Transcriptional Signature in Peripheral Blood Mononuclear Cells of Acute Renal Allograft Rejection. Front Med (Lausanne) 2022; 8:799051. [PMID: 35071278 PMCID: PMC8777044 DOI: 10.3389/fmed.2021.799051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
Acute rejection (AR) is closely associated with renal allograft dysfunction. Here, we utilised RNA sequencing (RNA-Seq) and bioinformatic methods to characterise the peripheral blood mononuclear cells (PBMCs) of patients with acute renal allograft rejection. Pretransplant blood samples were collected from 32 kidney allograft donors and 42 corresponding recipients with biopsies classified as T cell-mediated rejection (TCMR, n = 18), antibody-mediated rejection (ABMR, n = 5), and normal/non-specific changes (non-AR, n = 19). The patients with TCMR and ABMR were assigned to the AR group, and the patients with normal/non-specific changes (n = 19) were assigned to the non-AR group. We analysed RNA-Seq data for identifying differentially expressed genes (DEGs), and then gene ontology (GO) analysis, Reactome, and ingenuity pathway analysis (IPA), protein—protein interaction (PPI) network, and cell-type enrichment analysis were utilised for bioinformatics analysis. We identified DEGs in the PBMCs of the non-AR group when compared with the AR, ABMR, and TCMR groups. Pathway and GO analysis showed significant inflammatory responses, complement activation, interleukin-10 (IL-10) signalling pathways, classical antibody-mediated complement activation pathways, etc., which were significantly enriched in the DEGs. PPI analysis showed that IL-10, VEGFA, CXCL8, MMP9, and several histone-related genes were the hub genes with the highest degree scores. Moreover, IPA analysis showed that several proinflammatory pathways were upregulated, whereas antiinflammatory pathways were downregulated. The combination of NFSF14+TANK+ANKRD 33 B +HSPA1B was able to discriminate between AR and non-AR with an AUC of 92.3% (95% CI 82.8–100). Characterisation of PBMCs by RNA-Seq and bioinformatics analysis demonstrated gene signatures and biological pathways associated with AR. Our study may provide the foundation for the discovery of biomarkers and an in-depth understanding of acute renal allograft rejection.
Collapse
Affiliation(s)
- Wenyu Xiang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Shuai Han
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Cuili Wang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Hongjun Chen
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Lingling Shen
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Tingting Zhu
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Kai Wang
- School of Pharmaceutical Science, Sun Yat-sen University, Shenzhen, China
| | - Wenjie Wei
- Department of Nephropathy, School of Medicine, Shanghai Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jing Qin
- School of Pharmaceutical Science, Sun Yat-sen University, Shenzhen, China
| | - Nelli Shushakova
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Song Rong
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Hong Jiang
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| |
Collapse
|
|
49
|
Siegl J, Nikolin C, Phung NL, Thoms S, Blume C, Mayer G. Split-Combine Click-SELEX Reveals Ligands Recognizing the Transplant Rejection Biomarker CXCL9. ACS Chem Biol 2022; 17:129-137. [PMID: 35018777 DOI: 10.1021/acschembio.1c00789] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Renal rejection is a major incidence in patients after kidney transplantation and associated with allograft scarring and function loss, especially in antibody-mediated rejection. Regular clinical monitoring of kidney-transplanted patients is thus necessary, but measuring donor-specific antibodies is not always predictive, and graft biopsies are time-consuming and costly and may come up with a histological result unsuspicious for rejection. Therefore, a noninvasive diagnostic approach to estimate an increased probability of kidney graft rejection by measuring specific biomarkers is highly desired. The chemokine CXCL9 is described as an early indicator of rejection. In this work, we identified clickmers and an aptamer by split-combine click-SELEX (systematic evolution of ligands by exponential enrichment) that bind CXLC9 with high affinity. The aptamers recognize native CXCL9 and maintain binding properties under urine conditions. These features render the molecules as potential binding and detector probes for developing point-of-care devices, e.g., lateral flow assays, enabling the noninvasive monitoring of CXCL9 in renal allograft patients.
Collapse
Affiliation(s)
- Julia Siegl
- Chemical Biology & Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, Gerhard-Domagk-Str. 1, Bonn 53121, Germany
| | - Christoph Nikolin
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany
| | - Ngoc Linh Phung
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 5, Hannover 30167, Germany
| | - Stefanie Thoms
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 5, Hannover 30167, Germany
| | - Cornelia Blume
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 5, Hannover 30167, Germany
| | - Günter Mayer
- Chemical Biology & Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, Gerhard-Domagk-Str. 1, Bonn 53121, Germany
- Center of Aptamer Research & Development (CARD), University of Bonn, Gerhard-Domagk-Str. 1, Bonn 53121, Germany
| |
Collapse
|
|
50
|
Deville KA, Seifert ME. Biomarkers of alloimmune events in pediatric kidney transplantation. Front Pediatr 2022; 10:1087841. [PMID: 36741087 PMCID: PMC9895094 DOI: 10.3389/fped.2022.1087841] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/28/2022] [Indexed: 01/21/2023] Open
Abstract
Alloimmune events such as the development of de novo donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary contributors to kidney transplant failure in children. For decades, a creatinine-based estimated glomerular filtration rate (eGFR) has been the non-invasive gold standard biomarker for detecting clinically significant alloimmune events, but it suffers from low sensitivity and specificity, especially in smaller children and older allografts. Many clinically "stable" children (based on creatinine) will have alloimmune events known as "subclinical acute rejection" (based on biopsy) that merely reflect the inadequacy of creatinine-based estimates for alloimmune injury rather than a distinct phenotype from clinical rejection with allograft dysfunction. The poor biomarker performance of creatinine leads to many unnecessary surveillance and for-cause biopsies that could be avoided by integrating non-invasive biomarkers with superior sensitivity and specificity into current clinical paradigms. In this review article, we will present and appraise the current state-of-the-art in monitoring for alloimmune events in pediatric kidney transplantation. We will first discuss the current clinical standards for assessing the presence of alloimmune injury and predicting long-term outcomes. We will review principles of biomarker medicine and the application of comprehensive metrics to assess the performance of a given biomarker against the current gold standard. We will then highlight novel blood- and urine-based biomarkers (with special emphasis on pediatric biomarker studies) that have shown superior diagnostic and prognostic performance to the current clinical standards including creatinine-based eGFR. Finally, we will review some of the barriers to translating this research and implementing emerging biomarkers into common clinical practice, and present a transformative approach to using multiple biomarker platforms at different times to optimize the detection and management of critical alloimmune events in pediatric kidney transplant recipients.
Collapse
Affiliation(s)
- Kyle A Deville
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama Heersink School of Medicine, Birmingham, AL, United States
| | - Michael E Seifert
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama Heersink School of Medicine, Birmingham, AL, United States
| |
Collapse
|