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Clark AJ, Flores BM, Saade MC, Vu KQ, Pence IJ, Berg A, Parikh SM. Pediatric acute kidney injury is associated with impairment in nicotinamide adenine dinucleotide (NAD+) metabolism. Pediatr Nephrol 2025:10.1007/s00467-025-06791-5. [PMID: 40353859 DOI: 10.1007/s00467-025-06791-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 04/12/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Acute kidney injury (AKI) is highly prevalent among hospitalized children, but there is no treatment. Impaired de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis measured via elevation of the urine quinolinic acid-to-tryptophan ratio (uQ:T) is a feature of AKI that has been described in preclinical models and humans with AKI. Small prospective trials to restore NAD+ abundance with NAD+ precursor supplementation have shown promise in the prevention and treatment of AKI. It is not known whether pediatric patients also develop suppression of NAD+ biosynthesis during AKI, but such information will be critical before children can be included in NAD+ -based clinical trials to treat or prevent AKI. METHODS An observational cross-sectional study was performed on convenience urine samples from children hospitalized in a tertiary care children's hospital. Samples were split into five groups: outpatient controls, floor controls, ICU controls, floor AKI, and ICU AKI. Clinical data were collected from the medical record, and metabolites were measured using targeted mass spectrometry. Patients with AKI were compared to their respective controls. A multivariate linear regression was used to assess whether demographic variables were independently associated with uQ:T, and odds of AKI were assessed in serial uQ:T tertiles using multivariate logistic regression models that adjusted for patient variables. RESULTS Sixty-nine control patients (39 outpatient, 10 floor, and 20 ICU controls) and 22 AKI patients (12 floor and 10 ICU) were enrolled. uQ:T was elevated in patients with AKI compared to their respective controls. No demographic variables were independently associated with uQ:T, and when adjusting for patient demographic and clinical variables, the odds of AKI increased serially with uQ:T tertile. CONCLUSIONS Elevated uQ:T is a feature of pediatric AKI. The present results warrant further exploration in observational and potentially interventional studies with NAD+ precursor therapies.
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Affiliation(s)
- Amanda J Clark
- Pediatrics, Pediatric Nephrology and Children's Medical Center Dallas, University of Texas Southwestern, Dallas, USA.
| | - Brenda Mendoza Flores
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, USA
- Internal Medicine, Nephrology, University of Texas Southwestern, Dallas, USA
| | | | - Kyle Q Vu
- Pediatrics, Pediatric Nephrology and Children's Medical Center Dallas, University of Texas Southwestern, Dallas, USA
| | - Isaac J Pence
- Internal Medicine, Nephrology, University of Texas Southwestern, Dallas, USA
- Biomedical Engineering, University of Texas Southwestern, Dallas, USA
| | - Anders Berg
- Pathology, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Samir M Parikh
- Internal Medicine, Nephrology, University of Texas Southwestern, Dallas, USA
- Pharmacology, University of Texas Southwestern, Dallas, USA
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Baranovicova E, Vnucak M, Granak K, Kleinova P, Halasova E, Dedinska I. Assessment of metabolites in urine in post-kidney transplant patients: insights into allograft function and creatinine clearance. Metabolomics 2025; 21:44. [PMID: 40146357 PMCID: PMC11950123 DOI: 10.1007/s11306-025-02246-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/06/2025] [Indexed: 03/28/2025]
Abstract
INTRODUCTION The suboptimal function of transplanted kidney can lead to imbalances in processes controlled by the kidneys, necessitating long-term monitoring of the graft's function and viability. Given the kidneys' high metabolic activity, a metabolomics approach is well-suited for tracking changes in post-transplant patients and holds significant potential for monitoring graft function. OBJECTIVES Examination of the response of urinary creatinine levels to (i) serum creatinine levels and (ii) allograft function during periods of impaired kidney function in post-transplant patients. METHODS We analyzed morning and 24-h urine samples from 55 patients who underwent primary kidney transplantation and were uniformly treated with immunosuppressants, with an average follow-up of 50 months post-surgery. We assessed the relative levels of urinary metabolites detectable by NMR spectroscopy and investigated correlations between these metabolite levels and renal function. RESULTS We observed rather unexpected independence of urinary creatinine levels on levels of serum creatinine as well as on allograft function expressed by eGFR (estimated glomerular filtration rate). This observation allowed a very good agreement of outcomes from raw and creatinine-normalized data, consistent for both morning urine samples and 24-h urine collections. The urinary levels of citrate and acetone were detected to be sensitive to allograft function, and the urinary levels of metabolites in combination showed promising prediction for kidney function, on the level of p-value: for 24 h pooled urine: 4.6 × 10-12 and morning urine: 5.36 × 10-9. We discussed the data also in the light of metabolic changes in blood plasma. CONCLUSION We support the opinion of critical assessment of renal creatinine clearance when judging the filtration function of the allograft. As the next, urinary metabolomics can serve as an easily available supplement to prediction for allograft function in patients after kidney transplantation.
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Affiliation(s)
- Eva Baranovicova
- Biomedical Centre BioMed, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 036 01, Martin, Slovakia.
| | - Matej Vnucak
- Transplant-Nephrology Department and 1st Internal Department, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, Martin, Slovakia
| | - Karol Granak
- Transplant-Nephrology Department and 1st Internal Department, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, Martin, Slovakia
| | - Patricia Kleinova
- Transplant-Nephrology Department and 1st Internal Department, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, Martin, Slovakia
| | - Erika Halasova
- Biomedical Centre BioMed, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 036 01, Martin, Slovakia
| | - Ivana Dedinska
- Transplant-Nephrology Department and 1st Internal Department, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, Martin, Slovakia
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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.
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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
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Wang Y, Yu Z, Zhang Z, Mu R, Song J, Yang Z, Li R, Zhang J, Zhu X, Gong M, Wu X, Wang X. Integrating metabolomics with network pharmacology to reveal the mechanism of Poria cocos in hyperuricemia treatment. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118977. [PMID: 39433165 DOI: 10.1016/j.jep.2024.118977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 10/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hyperuricemia is a chronic condition characterized by persistently elevated uric acid levels, often leading to gouty arthritis and renal insufficiency. Poria cocos F.A.Wolf, a traditional Chinese medicinal herb, possesses notable diuretic and anti-inflammatory properties and is widely used to treat edema, inflammation, viral infections, and tumors. Recent studies suggest that Poria cocos has the potential to lower uric acid levels and mitigate kidney damage, making it a promising candidate for hyperuricemia treatment. However, its pharmacological mechanisms require further exploration. AIM OF THE STUDY This study aims to elucidate the mechanisms by which Poria cocos alleviates hyperuricemia, using metabolomics and network pharmacology approaches. MATERIALS AND METHODS Hyperuricemia was induced in rats via a high-yeast diet combined with potassium oxonate. The effects of Poria cocos were assessed by measuring serum uric acid, creatinine, urea nitrogen levels, hepatic xanthine oxidase activity, and renal tissue morphology. Non-targeted metabolomics was employed to identify differential metabolites and explore the metabolic pathways involved in its therapeutic effects. Network pharmacology was utilized to analyze potential targets and signaling pathways, which were validated through molecular docking and ELISA analysis. RESULTS Poria cocos extract significantly reduced serum uric acid, creatinine, and urea nitrogen levels, inhibited xanthine oxidase activity, and attenuated kidney damage. Metabolomics combined with network pharmacology identified xanthine dehydrogenase and fatty acid synthase as key targets, while purine metabolism, fatty acid biosynthesis, and primary bile acid biosynthesis were identified as critical pathways. ELISA confirmed that Poria cocos suppressed xanthine dehydrogenase and fatty acid synthase expression in hyperuricemic rats. Molecular docking further verified strong binding interactions between core compounds and key targets. CONCLUSIONS Poria cocos alleviates hyperuricemia by modulating multiple compounds, targets, and pathways. Through network pharmacology and metabolomics, it reveals that Poria cocos selectively regulates xanthine dehydrogenase and fatty acid synthase, influencing purine metabolism, fatty acid biosynthesis, and primary bile acid biosynthesis pathways. These findings provide insights into its therapeutic mechanisms, supporting the clinical application of Poria cocos in treating metabolic disorders and kidney damage associated with hyperuricemia.
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Affiliation(s)
- Yiru Wang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Zhijie Yu
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Zihao Zhang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Ronghui Mu
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Jiayin Song
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Zijun Yang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Rongshan Li
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Jun Zhang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Xuehui Zhu
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Min Gong
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaohui Wu
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
| | - Xu Wang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
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Alhumaidi R, Huang H, Saade MC, Clark AJ, Parikh SM. NAD + metabolism in acute kidney injury and chronic kidney disease transition. Trends Mol Med 2025:S1471-4914(24)00337-X. [PMID: 39757045 DOI: 10.1016/j.molmed.2024.12.004] [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: 09/12/2024] [Revised: 11/21/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025]
Abstract
Disturbances in kidney tubular cell metabolism are increasingly recognized as a feature of acute kidney injury (AKI). In AKI, tubular epithelial cells undergo abnormal metabolic shifts that notably disrupt NAD+ metabolism. Recent advancements have highlighted the critical role of NAD+ metabolism in AKI, revealing that acute disruptions may lead to lasting cellular changes, thereby promoting the transition to chronic kidney disease (CKD). This review explores the molecular mechanisms underlying metabolic dysfunction in AKI, with a focus on NAD+ metabolism, and proposes several cellular processes through which acute aberrations in NAD+ may contribute to long-term changes in the kidney.
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Affiliation(s)
- Rahil Alhumaidi
- Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Huihui Huang
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Marie Christelle Saade
- Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Amanda J Clark
- Division of Nephrology, Department of Pediatrics, University of Texas Southwestern and Children's Medical Center, Dallas, TX, USA
| | - Samir M Parikh
- Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Fu C, Zhang Y, Liang L, Lin H, Shan K, Liu F, Feng N. The microbiota in patients with interstitial cystitis/bladder pain syndrome: a systematic review. BJU Int 2024; 134:869-880. [PMID: 38890150 DOI: 10.1111/bju.16439] [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] [Indexed: 06/20/2024]
Abstract
OBJECTIVE To comprehensively review and critically assess the literature on microbiota differences between patients with interstitial cystitis (IC)/bladder pain syndrome (BPS) and normal controls and to provide clinical practice guidelines. MATERIALS AND METHODS In this systematic review, we evaluated previous research on microbiota disparities between IC/BPS and normal controls, as well as distinctions among IC/BPS subgroups. A comprehensive literature search was conducted across PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Relevant studies were shortlisted based on predetermined inclusion and exclusion criteria, followed by quality assessment. The primary focus was identifying specific taxonomic variations among these cohorts. RESULTS A total of 12 studies met the selection criteria. Discrepancies were adjudicated by a third reviewer. The Newcastle-Ottawa Scale was used to assess study quality. Predominantly, the studies focused on disparities in urine microbiota between IC/BPS patients and normal controls, with one study examining gut microbiota differences between the groups, and two studies exploring vaginal microbiota distinctions. Unfortunately, analyses of discrepancies in other microbiota were limited. Our findings revealed evidence of distinct bacterial abundance variations, particularly involving Lactobacillus, alongside variations in specific metabolites among IC/BPS patients compared to controls. CONCLUSIONS Currently, there is evidence suggesting significant variations in the diversity and species composition of the urinary microbiota between individuals diagnosed with IC/BPS and control groups. In the foreseeable future, urologists should consider urine microbiota dysbiosis as a potential aetiology for IC, with potential clinical implications for diagnosis and treatment.
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Affiliation(s)
- Chaowei Fu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yuwei Zhang
- Nantong University Medical School, Nantong, China
| | - Linghui Liang
- Department of Urology, Wuxi No. 2 Hospital, Nanjing Medical University, Wuxi, China
| | - Hao Lin
- Department of Urology, Wuxi No. 2 Hospital, Nanjing Medical University, Wuxi, China
| | - Kai Shan
- School of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Fengping Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Department of Urology, Jiangnan University Medical Center, Wuxi, China
| | - Ninghan Feng
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Department of Urology, Jiangnan University Medical Center, Wuxi, China
- Department of Urology, Wuxi No. 2 Hospital, Nanjing Medical University, Wuxi, China
- Nantong University Medical School, Nantong, China
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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.
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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
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8
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Laroche C, Engen RM. Immune monitoring in pediatric kidney transplant. Pediatr Transplant 2024; 28:e14785. [PMID: 38766986 DOI: 10.1111/petr.14785] [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: 03/09/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Long-term outcomes in pediatric kidney transplantation remain suboptimal, largely related to chronic rejection. Creatinine is a late marker of renal injury, and more sensitive, early markers of allograft injury are an active area of current research. METHODS This is an educational review summarizing existing strategies for monitoring for rejection in kidney transplant recipients. RESULTS We summarize supporting currently available clinical tests, including surveillance biopsy, donor specific antibodies, and donor-derived cell free DNA, as well as the potential limitations of these studies. In addition, we review the current avenues of active research, including transcriptomics, proteomics, metabolomics, and torque tenovirus levels. CONCLUSION Advancing the use of noninvasive immune monitoring will depend on well-designed multicenter trials that include patients with stable graft function, include biopsy results on all patients, and can demonstrate both association with a patient-relevant clinical endpoint such as graft survival or change in glomerular filtration rate and a potential timepoint for intervention.
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Affiliation(s)
| | - Rachel M Engen
- University of Wisconsin Madison, Madison, Wisconsin, USA
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9
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Clark AJ, Saade MC, Vemireddy V, Vu KQ, Flores BM, Etzrodt V, Ciampa EJ, Huang H, Takakura A, Zandi-Nejad K, Zsengellér ZK, Parikh SM. Hepatocyte nuclear factor 4α mediated quinolinate phosphoribosylltransferase (QPRT) expression in the kidney facilitates resilience against acute kidney injury. Kidney Int 2023; 104:1150-1163. [PMID: 37783445 PMCID: PMC10843022 DOI: 10.1016/j.kint.2023.09.013] [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: 06/05/2023] [Revised: 08/23/2023] [Accepted: 09/07/2023] [Indexed: 10/04/2023]
Abstract
Nicotinamide adenine dinucleotide (NAD+) levels decline in experimental models of acute kidney injury (AKI). Attenuated enzymatic conversion of tryptophan to NAD+ in tubular epithelium may contribute to adverse cellular and physiological outcomes. Mechanisms underlying defense of tryptophan-dependent NAD+ production are incompletely understood. Here we show that regulation of a bottleneck enzyme in this pathway, quinolinate phosphoribosyltransferase (QPRT) may contribute to kidney resilience. Expression of QPRT declined in two unrelated models of AKI. Haploinsufficient mice developed worse outcomes compared to littermate controls whereas novel, conditional gain-of-function mice were protected from injury. Applying these findings, we then identified hepatocyte nuclear factor 4 alpha (HNF4α) as a candidate transcription factor regulating QPRT expression downstream of the mitochondrial biogenesis regulator and NAD+ biosynthesis inducer PPARgamma coactivator-1-alpha (PGC1α). This was verified by chromatin immunoprecipitation. A PGC1α - HNF4α -QPRT axis controlled NAD+ levels across cellular compartments and modulated cellular ATP. These results propose that tryptophan-dependent NAD+ biosynthesis via QPRT and induced by HNF4α may be a critical determinant of kidney resilience to noxious stressors.
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Affiliation(s)
- Amanda J Clark
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA; Division of Nephrology, Department of Pediatrics, University of Texas Southwestern, Dallas, Texas, USA
| | - Marie Christelle Saade
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA
| | - Vamsidhara Vemireddy
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA
| | - Kyle Q Vu
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA
| | - Brenda Mendoza Flores
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA
| | - Valerie Etzrodt
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA
| | - Erin J Ciampa
- Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Huihui Huang
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Ayumi Takakura
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kambiz Zandi-Nejad
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Zsuzsanna K Zsengellér
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Samir M Parikh
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA; Department of Pharmacology, University of Texas Southwestern, Dallas, Texas, USA.
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10
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Rumbo M, Oltean M. Intestinal Transplant Immunology and Intestinal Graft Rejection: From Basic Mechanisms to Potential Biomarkers. Int J Mol Sci 2023; 24:ijms24054541. [PMID: 36901975 PMCID: PMC10003356 DOI: 10.3390/ijms24054541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Intestinal transplantation (ITx) remains a lifesaving option for patients suffering from irreversible intestinal failure and complications from total parenteral nutrition. Since its inception, it became obvious that intestinal grafts are highly immunogenic, due to their high lymphoid load, the abundance in epithelial cells and constant exposure to external antigens and microbiota. This combination of factors and several redundant effector pathways makes ITx immunobiology unique. To this complex immunologic situation, which leads to the highest rate of rejection among solid organs (>40%), there is added the lack of reliable non-invasive biomarkers, which would allow for frequent, convenient and reliable rejection surveillance. Numerous assays, of which several were previously used in inflammatory bowel disease, have been tested after ITx, but none have shown sufficient sensibility and/or specificity to be used alone for diagnosing acute rejection. Herein, we review and integrate the mechanistic aspects of graft rejection with the current knowledge of ITx immunobiology and summarize the quest for a noninvasive biomarker of rejection.
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Affiliation(s)
- Martin Rumbo
- Instituto de Estudios Inmunológicos y Fisiopatológicos, Facultad de Ciencias Exactas, Universidad Nacional de La Plata—CONICET, Boulevard 120 y 62, La Plata 1900, Argentina
| | - Mihai Oltean
- The Transplant Institute, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Surgery at Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, 413 90 Gothenburg, Sweden
- Correspondence:
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11
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Saade MC, Clark AJ, Parikh SM. States of quinolinic acid excess in urine: A systematic review of human studies. Front Nutr 2022; 9:1070435. [PMID: 36590198 PMCID: PMC9800835 DOI: 10.3389/fnut.2022.1070435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Quinolinic acid is an intermediate compound derived from the metabolism of dietary tryptophan. Its accumulation has been reported in patients suffering a broad spectrum of diseases and conditions. In this manuscript, we present the results of a systematic review of research studies assessing urinary quinolinic acid in health and disease. Methods We performed a literature review using PubMed, Cochrane, and Scopus databases of all studies reporting data on urinary quinolinic acid in human subjects from December 1949 to January 2022. Results Fifty-seven articles met the inclusion criteria. In most of the reported studies, compared to the control group, quinolinic acid was shown to be at increased concentration in urine of patients suffering from different diseases and conditions. This metabolite was also demonstrated to correlate with the severity of certain diseases including juvenile idiopathic inflammatory myopathies, graft vs. host disease, autism spectrum disorder, and prostate cancer. In critically ill patients, elevated quinolinic acid in urine predicted a spectrum of adverse outcomes including hospital mortality. Conclusion Quinolinic acid has been implicated in the pathophysiology of multiple conditions. Its urinary accumulation appears to be a feature of acute physiological stress and several chronic diseases. The exact significance of these findings is still under investigation, and further studies are needed to reveal the subsequent implications of this accumulation.
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Affiliation(s)
- Marie Christelle Saade
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, TX, United States
| | - Amanda J. Clark
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, TX, United States
- Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, United States
| | - Samir M. Parikh
- Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, TX, United States
- Department of Pharmacology, University of Texas Southwestern, Dallas, TX, United States
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12
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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.
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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,
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13
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Franiek A, Sharma A, Cockovski V, Wishart DS, Zappitelli M, Blydt-Hansen TD. Urinary metabolomics to develop predictors for pediatric acute kidney injury. Pediatr Nephrol 2022; 37:2079-2090. [PMID: 35006358 DOI: 10.1007/s00467-021-05380-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/21/2021] [Accepted: 11/18/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND Acute kidney injury (AKI) is characterized by an abrupt decline in glomerular filtration rate (GFR). We sought to identify separate early urinary metabolomic signatures at AKI onset (with-AKI) and prior to onset of functional impairment (pre-AKI). METHODS Pre-AKI (n=15), AKI (n=22), and respective controls (n=30) from two prospective PICU cohort studies provided urine samples which were analyzed by GC-MS and DI-MS mass spectrometry (193 metabolites). The cohort (n=58) was 8.7±6.4 years old and 66% male. AKI patients had longer PICU stays, higher PRISM scores, vasopressors requirement, and respiratory diagnosis and less commonly had trauma or post-operative diagnosis. Urine was collected within 2-3 days after admission and daily until day 5 or 14. RESULTS The metabolite classifiers for pre-AKI samples (1.5±1.1 days prior to AKI onset) had a cross-validated area under receiver operator curve (AUC)=0.93 (95%CI 0.85-1.0); with-AKI samples had an AUC=0.94 (95%CI 0.87-1.0). A parsimonious pre-AKI classifier with 13 metabolites was similarly robust (AUC=0.96, 95%CI 0.89-1.0). Both classifiers were similar and showed modest correlation of high-ranking metabolites (tau=0.47, p<0.001). CONCLUSIONS This exploratory study demonstrates the potential of a urine metabolite classifier to detect AKI-risk in pediatric populations earlier than the current standard of diagnosis with the need for external validation. A higher resolution version of the Graphical abstract is available as Supplementary information with inner reference to ESM for GA.
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Affiliation(s)
- Alexandra Franiek
- College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Atul Sharma
- Department of Pediatrics and Child Health, Children's Hospital at Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada
| | - Vedran Cockovski
- SickKids Research Institute, University of Toronto, Toronto, ON, Canada
| | - David S Wishart
- The Metabolomics Innovation Center, University of Alberta, Edmonton, AB, Canada
| | - Michael Zappitelli
- Department of Pediatrics, Division of Nephrology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Québec, Canada
| | - Tom D Blydt-Hansen
- Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.
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14
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Rinaldi A, Lazareth H, Poindessous V, Nemazanyy I, Sampaio JL, Malpetti D, Bignon Y, Naesens M, Rabant M, Anglicheau D, Cippà PE, Pallet N. Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury. JCI Insight 2022; 7:161783. [PMID: 35998043 DOI: 10.1172/jci.insight.161783] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022] Open
Abstract
Energy metabolism failure in proximal tubule cells (PTC) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic and lipidomic approaches in experimental models and patient cohorts to investigate the molecular bases of the progression to chronic kidney allograft injury initiated by ischemia-reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was significantly enriched with long chain fatty acids (FA). We identified a renal FA-related gene signature with low levels of Cpt2 and Acsm5 and high levels of Acsl4 and Acsm5 associated with IRI, transition to chronic injury, and established CKD in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2-, Acsl4+, Acsl5+, Acsm5- PTC failing to recover from IRI as identified by snRNAseq. In vitro experiments indicated that endoplasmic reticulum (ER) stress contributes to CPT2 repression, which, in turn, promotes lipids accumulation, drives profibrogenic epithelial phenotypic changes, and activates the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation, engages an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule sustaining the progression to chronic kidney allograft injury.
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Affiliation(s)
- Anna Rinaldi
- Department of Medicine, Division of Nephrology, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Hélène Lazareth
- Centre de Recherche des Cordeliers, INSERM U1138, Paris, France
| | | | - Ivan Nemazanyy
- PMM: The Metabolism-Metabolome Platform, Necker Federative Research Structu, INSERM US24/CNRS, UMS3633, Paris, France
| | - Julio L Sampaio
- CurieCoreTech Metabolomics and Lipidomics Technology Platform, Paris, France
| | - Daniele Malpetti
- Instituto Dalle Molle di Studi sull'Intelligenza Artificiale, Lugano, Switzerland
| | - Yohan Bignon
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Marion Rabant
- Department of Pathology, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Dany Anglicheau
- Department of Kidney Transplantation, Necker Hospital, Paris, France
| | - Pietro E Cippà
- Department of Medicine, Division of Nephrology, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Nicolas Pallet
- Centre de Recherche des Cordeliers, INSERM U1138, Paris, France
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15
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Circulating Metabolites in Relation to the Kidney Allograft Function in Posttransplant Patients. Metabolites 2022; 12:metabo12070661. [PMID: 35888785 PMCID: PMC9318187 DOI: 10.3390/metabo12070661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/14/2022] [Accepted: 07/14/2022] [Indexed: 12/05/2022] Open
Abstract
End-stage kidney disease is preferably treated by kidney transplantation. The suboptimal function of the allograft often results in misbalances in kidney-controlled processes and requires long-term monitoring of allograft function and viability. As the kidneys are organs with a very high metabolomic rate, a metabolomics approach is suitable to describe systematic changes in post-transplant patients and has great potential for monitoring allograft function, which has not been described yet. In this study, we used blood plasma samples from 55 patients after primary kidney transplantation identically treated with immunosuppressants with follow-up 50 months in the mean after surgery and evaluated relative levels of basal plasma metabolites detectable by NMR spectroscopy. We were looking for the correlations between circulating metabolites levels and allograft performance and allograft rejection features. Our results imply a quantitative relationship between restricted renal function, insufficient hydroxylation of phenylalanine to tyrosine, lowered renal glutamine utilization, shifted nitrogen balance, and other alterations that are not related exclusively to the metabolism of the kidney. No link between allograft function and energy metabolism can be concluded, as no changes were found for glucose, glycolytic intermediates, and 3-hydroxybutyrate as a ketone body representative. The observed changes are to be seen as a superposition of changes in the comprehensive inter-organ metabolic exchange, when the restricted function of one organ may induce compensatory effects or cause secondary alterations. Particular differences in plasma metabolite levels in patients with acute cellular and antibody-mediated allograft rejection were considered rather to be related to the loss of kidney function than to the molecular mechanism of graft rejection since they largely follow the alterations observed by restricted allograft function. In the end, we showed using a simple mathematical model, multilinear regression, that the basal plasmatic metabolites correlated with allograft function expressed by the level of glomerular filtration rate (with creatinine: p-value = 4.0 × 10−26 and r = 0.94, without creatinine: p-value = 3.2 × 10−22 and r = 0.91) make the noninvasive estimation of the allograft function feasible.
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16
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Riccio S, Valentino MS, Passaro AP, Izzo M, Guarino S, Miraglia del Giudice E, Marzuillo P, Di Sessa A. New Insights from Metabolomics in Pediatric Renal Diseases. CHILDREN (BASEL, SWITZERLAND) 2022; 9:118. [PMID: 35053744 PMCID: PMC8774568 DOI: 10.3390/children9010118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 12/11/2022]
Abstract
Renal diseases in childhood form a spectrum of different conditions with potential long-term consequences. Given that, a great effort has been made by researchers to identify candidate biomarkers that are able to influence diagnosis and prognosis, in particular by using omics techniques (e.g., metabolomics, lipidomics, genomics, and transcriptomics). Over the past decades, metabolomics has added a promising number of 'new' biomarkers to the 'old' group through better physiopathological knowledge, paving the way for insightful perspectives on the management of different renal diseases. We aimed to summarize the most recent omics evidence in the main renal pediatric diseases (including acute renal injury, kidney transplantation, chronic kidney disease, renal dysplasia, vesicoureteral reflux, and lithiasis) in this narrative review.
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Affiliation(s)
| | | | | | | | | | | | | | - Anna Di Sessa
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.R.); (M.S.V.); (A.P.P.); (M.I.); (S.G.); (E.M.d.G.); (P.M.)
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17
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Verissimo T, Faivre A, Sgardello S, Naesens M, de Seigneux S, Criton G, Legouis D. Estimated Renal Metabolomics at Reperfusion Predicts One-Year Kidney Graft Function. Metabolites 2022; 12:57. [PMID: 35050179 PMCID: PMC8778290 DOI: 10.3390/metabo12010057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/26/2021] [Accepted: 01/04/2022] [Indexed: 02/04/2023] Open
Abstract
Renal transplantation is the gold-standard procedure for end-stage renal disease patients, improving quality of life and life expectancy. Despite continuous advancement in the management of post-transplant complications, progress is still needed to increase the graft lifespan. Early identification of patients at risk of rapid graft failure is critical to optimize their management and slow the progression of the disease. In 42 kidney grafts undergoing protocol biopsies at reperfusion, we estimated the renal metabolome from RNAseq data. The estimated metabolites' abundance was further used to predict the renal function within the first year of transplantation through a random forest machine learning algorithm. Using repeated K-fold cross-validation we first built and then tuned our model on a training dataset. The optimal model accurately predicted the one-year eGFR, with an out-of-bag root mean square root error (RMSE) that was 11.8 ± 7.2 mL/min/1.73 m2. The performance was similar in the test dataset, with a RMSE of 12.2 ± 3.2 mL/min/1.73 m2. This model outperformed classic statistical models. Reperfusion renal metabolome may be used to predict renal function one year after allograft kidney recipients.
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Affiliation(s)
- Thomas Verissimo
- Laboratory of Nephrology, Department of Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; (T.V.); (A.F.); (S.d.S.)
| | - Anna Faivre
- Laboratory of Nephrology, Department of Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; (T.V.); (A.F.); (S.d.S.)
| | - Sebastian Sgardello
- Department of Surgery, University Hospital of Geneva, 1205 Geneva, Switzerland;
| | - Maarten Naesens
- Service of Nephrology, University Hospitals of Leuven, 3000 Leuven, Belgium;
| | - Sophie de Seigneux
- Laboratory of Nephrology, Department of Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; (T.V.); (A.F.); (S.d.S.)
- Service of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, 1205 Geneva, Switzerland
| | - Gilles Criton
- Geneva School of Economics and Management, University of Geneva, 1205 Geneva, Switzerland;
| | - David Legouis
- Laboratory of Nephrology, Department of Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; (T.V.); (A.F.); (S.d.S.)
- Division of Intensive Care, Department of Acute Medicine, University hospital of Geneva, 1205 Geneva, Switzerland
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18
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Banas MC, Böhmig GA, Viklicky O, Rostaing LP, Jouve T, Guirado L, Facundo C, Bestard O, Gröne HJ, Kobayashi K, Hanzal V, Putz FJ, Zecher D, Bergler T, Neumann S, Rothe V, Schwäble Santamaria AG, Schiffer E, Banas B. A Prospective Multicenter Trial to Evaluate Urinary Metabolomics for Non-invasive Detection of Renal Allograft Rejection (PARASOL): Study Protocol and Patient Recruitment. Front Med (Lausanne) 2022; 8:780585. [PMID: 35071266 PMCID: PMC8782243 DOI: 10.3389/fmed.2021.780585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/01/2021] [Indexed: 12/29/2022] Open
Abstract
Background: In an earlier monocentric study, we have developed a novel non-invasive test system for the prediction of renal allograft rejection, based on the detection of a specific urine metabolite constellation. To further validate our results in a large real-world patient cohort, we designed a multicentric observational prospective study (PARASOL) including six independent European transplant centers. This article describes the study protocol and characteristics of recruited better patients as subjects. Methods: Within the PARASOL study, urine samples were taken from renal transplant recipients when kidney biopsies were performed. According to the Banff classification, urine samples were assigned to a case group (renal allograft rejection), a control group (normal renal histology), or an additional group (kidney damage other than rejection). Results: Between June 2017 and March 2020, 972 transplant recipients were included in the trial (1,230 urine samples and matched biopsies, respectively). Overall, 237 samples (19.3%) were assigned to the case group, 541 (44.0%) to the control group, and 452 (36.7%) samples to the additional group. About 65.9% were obtained from male patients, the mean age of transplant recipients participating in the study was 53.7 ± 13.8 years. The most frequently used immunosuppressive drugs were tacrolimus (92.8%), mycophenolate mofetil (88.0%), and steroids (79.3%). Antihypertensives and antidiabetics were used in 88.0 and 27.4% of the patients, respectively. Approximately 20.9% of patients showed the presence of circulating donor-specific anti-HLA IgG antibodies at time of biopsy. Most of the samples (51.1%) were collected within the first 6 months after transplantation, 48.0% were protocol biopsies, followed by event-driven (43.6%), and follow-up biopsies (8.5%). Over time the proportion of biopsies classified into the categories Banff 4 (T-cell-mediated rejection [TCMR]) and Banff 1 (normal tissue) decreased whereas Banff 2 (antibody-mediated rejection [ABMR]) and Banff 5I (mild interstitial fibrosis and tubular atrophy) increased to 84.2 and 74.5%, respectively, after 4 years post transplantation. Patients with rejection showed worse kidney function than patients without rejection. Conclusion: The clinical characteristics of subjects recruited indicate a patient cohort typical for routine renal transplantation all over Europe. A typical shift from T-cellular early rejections episodes to later antibody mediated allograft damage over time after renal transplantation further strengthens the usefulness of our cohort for the evaluation of novel biomarkers for allograft damage.
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Affiliation(s)
- Miriam C. Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
- Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
| | - Lionel P. Rostaing
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, Grenoble, France
- Faculty of Health, Grenoble Alpes University, Grenoble, France
| | - Thomas Jouve
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, Grenoble, France
| | - Lluis Guirado
- Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Medicine Department-Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Carme Facundo
- Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Medicine Department-Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Oriol Bestard
- Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | | | | | - Vladimir Hanzal
- Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
| | - Franz Josef Putz
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Daniel Zecher
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Tobias Bergler
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | | | | | | | | | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
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Yatim KM, Azzi JR. Novel Biomarkers in Kidney Transplantation. Semin Nephrol 2022; 42:2-13. [DOI: 10.1016/j.semnephrol.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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20
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Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children. Transplant Direct 2021; 7:e791. [PMID: 34805493 PMCID: PMC8601357 DOI: 10.1097/txd.0000000000001244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/13/2021] [Accepted: 09/17/2021] [Indexed: 11/23/2022] Open
Abstract
Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients.
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Chimerism and tolerance: past, present and future strategies to prolong renal allograft survival. Curr Opin Nephrol Hypertens 2021; 30:63-74. [PMID: 33186221 DOI: 10.1097/mnh.0000000000000666] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Immunological factors are a major cause of kidney allograft loss. Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival; however, they in turn contribute to long-term kidney allograft loss from chronic CNI nephrotoxicity. Tolerance induction in transplantation can avoid the long-term adverse effects of immunosuppressive medications. This review aims to critically discuss recent efforts in inducing transplantation tolerance. RECENT FINDINGS Tolerance induction mediated by chimerism has shown some promise in minimizing or even complete withdrawal of immunosuppressive treatments in kidney allograft recipients. There has been a number of approaches as varied as the number of centres conducting these trials. However, they can be grouped into those mediated by transient microchimerism and those facilitated by more stable macro or full donor chimerism. The success rates in terms of long-term drug-free graft survival has been limited in microchimerism-mediated tolerance induction approaches. Mixed macrochimerism of less than 50% donor may be unstable with mostly the recipient's native immune system overpowering the donor chimeric status.Tolerance induction leading to chimerism has been limited to living donor kidney transplantation and additional long-term outcomes are required. Furthermore, immune monitoring after tolerance induction has faced a limitation in studying due to a lack of sufficient study participants and appropriate study controls. SUMMARY Tolerance induction is one of several strategies used to prolong kidney allograft survival, but it has not been routinely utilized in clinical practice. However, future applications from the trials to clinical practice remain limited to living donor kidney transplantation. Once further data regarding tolerance inductions exist and practicality becomes widely accepted, tolerance induction may shift the paradigm in the field of kidney transplantation to achieve the best possible outcome of 'One Organ for Life'.
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Snopkowski C, Salinas T, Li C, Stryjniak G, Ding R, Sharma V, Suthanthiran M. Urinary cell mRNA profiling of kidney allograft recipients: A systematic investigation of a filtration based protocol for the simplification of urine processing. J Immunol Methods 2021; 498:113132. [PMID: 34464607 PMCID: PMC8487946 DOI: 10.1016/j.jim.2021.113132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/27/2021] [Accepted: 08/24/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Kidney transplantation is a life-restorative therapy, but immune rejection undermines allograft survival. Urinary cell mRNA profiles offer a noninvasive means of diagnosing kidney allograft rejection, but urine processing protocols have logistical constraints. We aimed to determine whether the centrifugation-based method for urinary cell mRNA profiling could be replaced with a simpler filtration-based method without undermining quality. METHODS We isolated RNA from urine collected from kidney allograft recipients using the Cornell centrifugation-based protocol (CCBP) or the Zymo filter-based protocol (ZFBP) and compared RNA purity and yield using a spectrophotometer or a fluorometer and measured absolute copy number of transcripts using customized real-time quantitative PCR assays. We investigated the performance characteristics of RNA isolated using ZFBP and stored either at -80 °C or at ambient temperature for 2 to 4 days and also when shipped to our Gene Expression Monitoring (GEM) Core at ambient temperature. We examined the feasibility of initial processing of urine samples by kidney allograft recipients trained by the GEM Core staff and the diagnostic utility for acute rejection, of urine processed using the ZFBP. RESULTS RNA purity (P = 0.0007, Wilcoxon matched paired signed-ranks test) and yield (P < 0.0001) were higher with ZFBP vs. CCBP, and absolute copy number of 18S rRNA was similar (P = 0.79) following normalization of RNA yield by reverse transcribing a constant amount of RNA isolated using either protocol. RNA purity, yield, and absolute copy numbers of 18S rRNA, TGF-β1 mRNA and microRNA-26a were not different (P > 0.05) in the filtrates containing RNA stored either at -80 °C or at ambient temperature for 2 to 4 days or shipped overnight at ambient temperature. RNA purity, yield, and absolute copy numbers of 18S rRNA and TGF-β1 mRNA were also not different (P > 0.05) between home processed and laboratory processed urine filtrates. Urinary cell levels of mRNA for granzyme B (P = 0.01) and perforin (P = 0.0002) in the filtrates were diagnostic of acute rejection in human kidney allografts. CONCLUSIONS Urinary cell mRNA profiling was simplified using the ZFBP without undermining RNA quality or diagnostic utility. Home processing by the kidney allograft recipients, the stability of RNA containing filtrates at ambient temperature, and the elimination of the need for centrifuges and freezers represent some of the advantages of ZFBP over the CCBP for urinary cell mRNA profiling.
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Affiliation(s)
- Catherine Snopkowski
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Thalia Salinas
- 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
| | - Carol Li
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Gabriel Stryjniak
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Ruchuang Ding
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Vijay Sharma
- Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-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.
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23
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Lubetzky ML, Salinas T, Schwartz JE, Suthanthiran M. Urinary Cell mRNA Profiles Predictive of Human Kidney Allograft Status. Clin J Am Soc Nephrol 2021; 16:1565-1577. [PMID: 33906907 PMCID: PMC8499006 DOI: 10.2215/cjn.14010820] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Immune monitoring of kidney allograft recipients and personalized therapeutics may help reach the aspirational goal of "one transplant for life." The invasive kidney biopsy procedure, the diagnostic tool of choice, has become safer and the biopsy classification more refined. Nevertheless, biopsy-associated complications, interobserver variability in biopsy specimen scoring, and costs continue to be significant concerns. The dynamics of the immune repertoire make frequent assessments of allograft status necessary, but repeat biopsies of the kidney are neither practical nor safe. To address the existing challenges, we developed urinary cell mRNA profiling and investigated the diagnostic, prognostic, and predictive accuracy of absolute levels of a hypothesis-based panel of mRNAs encoding immunoregulatory proteins. Enabled by our refinements of the PCR assay and by investigating mechanistic hypotheses, our single-center studies identified urinary cell mRNAs associated with T cell-mediated rejection, antibody-mediated rejection, interstitial fibrosis and tubular atrophy, and BK virus nephropathy. In the multicenter National Institutes of Health Clinical Trials in Organ Transplantation-04, we discovered and validated a urinary cell three-gene signature of T-cell CD3 ε chain mRNA, interferon gamma inducible protein 10 (IP-10) mRNA, and 18s ribosomal RNA that is diagnostic of subclinical acute cellular rejection and acute cellular rejection and prognostic of acute cellular rejection and graft function. The trajectory of the signature score remained flat and below the diagnostic threshold for acute cellular rejection in the patients with no rejection biopsy specimens, whereas a sharp rise was observed during the weeks before the biopsy specimen that showed acute cellular rejection. Our RNA sequencing and bioinformatics identified kidney allograft biopsy specimen gene signatures of acute rejection to be enriched in urinary cells matched to acute rejection biopsy specimens. The urinary cellular landscape was more diverse and more enriched for immune cell types compared with kidney allograft biopsy specimens. Urinary cell mRNA profile-guided clinical trials are needed to evaluate their value compared with current standard of care.
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Affiliation(s)
- Michelle L. Lubetzky
- Division of Nephrology and Hypertension, Weill Cornell Department of Medicine, New York, New York,Department of Transplantation Medicine, New York–Presbyterian Hospital, New York, New York
| | - Thalia Salinas
- Division of Nephrology and Hypertension, Weill Cornell Department of Medicine, New York, New York,Department of Transplantation Medicine, New York–Presbyterian Hospital, New York, New York
| | - Joseph E. Schwartz
- Division of Nephrology and Hypertension, Weill Cornell Department of Medicine, New York, New York,Department of Transplantation Medicine, New York–Presbyterian Hospital, New York, New York,Department of Psychiatry and Behavioral Sciences, Stony Brook Renaissance School of Medicine, Stony Brook, New York
| | - Manikkam Suthanthiran
- Division of Nephrology and Hypertension, Weill Cornell Department of Medicine, New York, New York,Department of Transplantation Medicine, New York–Presbyterian Hospital, New York, New York
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24
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Ehlayel A, Simms KJA, Ashoor IF. Emerging monitoring technologies in kidney transplantation. Pediatr Nephrol 2021; 36:3077-3087. [PMID: 33523298 DOI: 10.1007/s00467-021-04929-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/22/2020] [Accepted: 01/06/2021] [Indexed: 11/27/2022]
Abstract
Non-invasive technologies to monitor kidney allograft health utilizing high-throughput assays of blood and urine specimens are emerging out of the research realm and slowly becoming part of everyday clinical practice. HLA epitope analysis and eplet mismatch score determination promise a more refined approach to the pre-transplant recipient-donor HLA matching that may lead to reduced rejection risk. High-resolution HLA typing and multiplex single antigen bead assays are identifying potential new offending HLA antibody subtypes. There is increasing recognition of the deleterious role non-HLA antibodies play in post-transplant outcomes. Donor-derived cell-free DNA detected by next-generation sequencing is a promising biomarker for kidney transplant rejection. Multi-omics techniques are shedding light on discrete genomic, transcriptomic, proteomic, and metabolomic signatures that correlate with and predict allograft outcomes. Over the next decade, a comprehensive approach to optimize kidney matching and monitor transplant recipients for acute and chronic graft dysfunction will likely involve a combination of those emerging technologies summarized in this review.
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Affiliation(s)
- Abdulla Ehlayel
- Children's Hospital New Orleans, 200 Henry Clay Ave, New Orleans, LA, 70118, USA
| | - K'joy J A Simms
- Children's Hospital New Orleans, 200 Henry Clay Ave, New Orleans, LA, 70118, USA
| | - Isa F Ashoor
- Children's Hospital New Orleans, 200 Henry Clay Ave, New Orleans, LA, 70118, USA.
- Department of Pediatrics, LSU Health New Orleans, 200 Henry Clay Ave, New Orleans, LA, 70118, USA.
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25
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Xu H, Tamrat NE, Gao J, Xu J, Zhou Y, Zhang S, Chen Z, Shao Y, Ding L, Shen B, Wei Z. Combined Signature of the Urinary Microbiome and Metabolome in Patients With Interstitial Cystitis. Front Cell Infect Microbiol 2021; 11:711746. [PMID: 34527602 PMCID: PMC8436771 DOI: 10.3389/fcimb.2021.711746] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/29/2021] [Indexed: 02/02/2023] Open
Abstract
Interstitial cystitis (IC) is a clinical syndrome characterized by frequency, urgency, and bladder pain or pelvic pain; however, the underlying pathophysiological mechanisms and diagnostic markers are unknown. In this study, microbiome and metabolome analysis were used to explain the urine signatures of IC patients. Urine samples from 20 IC patients and 22 control groups were analyzed by using 16S rRNA sequence and liquid chromatography coupled with mass spectrometry. Four opportunistic pathogen genera, including Serratia, Brevibacterium, Porphyromonas, and Citrobacter, were significantly upregulated in IC group. The altered metabolite signatures of the metabolome may be related to sphingosine metabolism, amino acid metabolism, and fatty acid biosynthesis. Meanwhile, the associations were observed between different metabolites and microbiomes of IC. The present study suggests that the combined signatures of IC in urine microbiome and metabolome may become its prospective diagnostic markers.
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Affiliation(s)
- Hewei Xu
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Nebiyu Elias Tamrat
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Jie Gao
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Jie Xu
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Yiduo Zhou
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Sicong Zhang
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Zhengsen Chen
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Yunpeng Shao
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Liucheng Ding
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Baixin Shen
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Zhongqing Wei
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Urology, The Second Clinical Medical College of Nanjing Medical University, Nanjing, China
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26
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Başak Oktay S, Akbaş SH, Yilmaz VT, Özen Küçükçetin İ, Toru HS, Yücel SG. Association Between Graft Function and Urine CXCL10 and Acylcarnitines Levels in Kidney Transplant Recipients. Lab Med 2021; 53:78-84. [PMID: 34388247 DOI: 10.1093/labmed/lmab049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To evaluate post-transplantation graft functions noninvasively by using urine C-X-C motif chemokine 10 (CXCL10) and metabolome analysis. METHODS The 65 living-donor kidney-transplant recipients in our cohort underwent renal biopsy to investigate possible graft dysfunction. The patients were divided into 2 groups, according to pathology reports: chronic allograft dysfunction (CAD; n = 18) and antibody-mediated/humoral allograft rejection (AMR; n = 16). The control group was composed of renal transplant recipients with stable health (n = 33). We performed serum creatinine, blood urea nitrogen (BUN), cystatin C, urine protein, CXCL10, and metabolome analyses on specimens from the patients. RESULTS BUN, creatinine, cystatin C, urine protein, leucine + isoleucine, citrulline, and free/acetyl/propionyl carnitine levels were significantly higher in patients with CAD and AMR, compared with the control individuals. CXCL10 levels were significantly elevated in patients with AMR, compared with patients with CAD and controls. CXCL10 (AUC = 0.771) and cystatin C (AUC = 0.746) were significantly higher in the AMR group, compared with the CAD group (P<.02). CONCLUSIONS CXCL10 and metabolome analyzes are useful for evaluation of graft functions. Also, CXCL10 might be useful as a supplementary noninvasive screening test for diagnosis of allograft rejection.
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Affiliation(s)
- Saniye Başak Oktay
- Department of Biochemistry, Adıyaman University Education and Research Hospital, Adıyaman, Turkey
| | | | | | | | - Havva Serap Toru
- Department of Pathology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
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27
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Kidney Allograft Function Is a Confounder of Urine Metabolite Profiles in Kidney Allograft Recipients. Metabolites 2021; 11:metabo11080533. [PMID: 34436474 PMCID: PMC8399888 DOI: 10.3390/metabo11080533] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/24/2021] [Accepted: 08/03/2021] [Indexed: 11/17/2022] Open
Abstract
Noninvasive biomarkers of kidney allograft status can help minimize the need for standard of care kidney allograft biopsies. Metabolites that are measured in the urine may inform about kidney function and health status, and potentially identify rejection events. To test these hypotheses, we conducted a metabolomics study of biopsy-matched urine cell-free supernatants from kidney allograft recipients who were diagnosed with two major types of acute rejections and no-rejection controls. Non-targeted metabolomics data for 674 metabolites and 577 unidentified molecules, for 192 biopsy-matched urine samples, were analyzed. Univariate and multivariate analyses identified metabolite signatures for kidney allograft rejection. The replicability of a previously developed urine metabolite signature was examined. Our study showed that metabolite profiles can serve as biomarkers for discriminating rejection biopsies from biopsies without rejection features, but also revealed a role of estimated Glomerular Filtration Rate (eGFR) as a major confounder of the metabolite signal.
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28
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Wang T, Tang L, Lin R, He D, Wu Y, Zhang Y, Yang P, He J. Individual variability in human urinary metabolites identifies age-related, body mass index-related, and sex-related biomarkers. Mol Genet Genomic Med 2021; 9:e1738. [PMID: 34293245 PMCID: PMC8404239 DOI: 10.1002/mgg3.1738] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 05/05/2019] [Accepted: 05/22/2019] [Indexed: 12/14/2022] Open
Abstract
Background Metabolites present in human urine can be influenced by individual physiological parameters (e.g., body mass index [BMI], age, and sex). Observation of altered metabolites concentrations could provide insight into underlying disease pathology, disease prognosis and diagnosis, and facilitate discovery of novel biomarkers. Methods Quantitative metabolomics analysis in the urine of 183 healthy individuals was performed based on high‐resolution liquid chromatography–mass spectrometry (LC–MS). Coefficients of variation were obtained for 109 urine metabolites of all the 183 human healthy subjects. Results Three urine metabolites (such as dehydroepiandrosterone sulfate, acetaminophen glucuronide, and p‐anisic acid) with CV183 > 0.3, for which metabolomics studies have been scarce, are considered highly variable here. We identified 30 age‐related metabolites, 18 BMI‐related metabolites, and 42 sex‐related metabolites. Among the identified metabolites, three metabolites were found to be associated with all three physiological parameters (age, BMI, and sex), which included dehydroepiandrosterone sulfate, 3‐methylcrotonylglycine and N‐acetyl‐aspartic acid. Pearson's coefficients demonstrated that some age‐, BMI‐, and sex‐related compounds are strongly correlated, suggesting that age, BMI, and sex could affect them concomitantly. Conclusion Metabolic differences between distinct physiological statuses were found to be related to several metabolic pathways (such as the caffeine metabolism, the amino acid metabolism, and the carbohydrate metabolism), and these findings may be key for the discovery of new diagnostics and treatments as well as new understandings on the mechanisms of some related diseases.
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Affiliation(s)
- Tianling Wang
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China.,Dingxi Campus of Gansu, University of Traditional Chinese Medicine, Dingxi, China
| | - Lei Tang
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China
| | - Ruili Lin
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China
| | - Dian He
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China.,Gansu Institute for Drug Control, Lanzhou, China
| | - Yanqing Wu
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China
| | - Yang Zhang
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China.,School of Pharmaceutical Sciences, Chongqing University, Chongqing, China
| | - Pingrong Yang
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China.,Gansu Institute for Drug Control, Lanzhou, China
| | - Junquan He
- Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, China.,Gansu Institute for Drug Control, Lanzhou, China
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29
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Schultheiss UT, Kosch R, Kotsis F, Altenbuchinger M, Zacharias HU. Chronic Kidney Disease Cohort Studies: A Guide to Metabolome Analyses. Metabolites 2021; 11:460. [PMID: 34357354 PMCID: PMC8304377 DOI: 10.3390/metabo11070460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Kidney diseases still pose one of the biggest challenges for global health, and their heterogeneity and often high comorbidity load seriously hinders the unraveling of their underlying pathomechanisms and the delivery of optimal patient care. Metabolomics, the quantitative study of small organic compounds, called metabolites, in a biological specimen, is gaining more and more importance in nephrology research. Conducting a metabolomics study in human kidney disease cohorts, however, requires thorough knowledge about the key workflow steps: study planning, sample collection, metabolomics data acquisition and preprocessing, statistical/bioinformatics data analysis, and results interpretation within a biomedical context. This review provides a guide for future metabolomics studies in human kidney disease cohorts. We will offer an overview of important a priori considerations for metabolomics cohort studies, available analytical as well as statistical/bioinformatics data analysis techniques, and subsequent interpretation of metabolic findings. We will further point out potential research questions for metabolomics studies in the context of kidney diseases and summarize the main results and data availability of important studies already conducted in this field.
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Affiliation(s)
- Ulla T. Schultheiss
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany; (U.T.S.); (F.K.)
- Department of Medicine IV—Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Robin Kosch
- Computational Biology, University of Hohenheim, 70599 Stuttgart, Germany;
| | - Fruzsina Kotsis
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany; (U.T.S.); (F.K.)
- Department of Medicine IV—Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Michael Altenbuchinger
- Institute of Medical Bioinformatics, University Medical Center Göttingen, 37077 Göttingen, Germany;
| | - Helena U. Zacharias
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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Multi-Solvent Extraction Procedure for the Pioneer Fecal Metabolomic Analysis-Identification of Potential Biomarkers in Stable Kidney Transplant Patients. Diagnostics (Basel) 2021; 11:diagnostics11060962. [PMID: 34073647 PMCID: PMC8229050 DOI: 10.3390/diagnostics11060962] [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: 03/31/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 11/21/2022] Open
Abstract
Metabolic alteration plays a functional role in kidney allograft complications. Metabolomics is a promising high-throughput approach in nephrology but is still limited by the lack of overlap in metabolite coverage. We performed an untargeted fecal metabolomic analysis of forty stable kidney allograft recipients and twenty non-transplant controls. First, we applied the ultra-high performance liquid chromatography (UHPLC) analysis coupled with the Diod Array detector. The potential biomarkers were then collected and identified by gas chromatography-mass spectrometry (GCMS). In order to allow for complete coverage of the fecal polar and non-polar metabolites, the performance of five organic solvents with increasing polarity was investigated successively. UHPLC analysis revealed that the fecal metabolite profiles following the five extractions were significantly different between controls and kidney allografts. GC-MS analysis showed that the best predictors’ metabolites belonged mainly to long-chain fatty acids, phenolic compounds, and amino acids. Collectively, our results showed the efficiency of our pioneer method to successfully discriminate stable kidney-transplant recipients from controls. These findings suggest that distinct metabolic profiles mainly affect fatty acid biosynthesis and amino acid metabolism. In such a context, the novel insights into metabolomic investigation may be a valuable tool that could provide useful new relevant biomarkers for preventing kidney transplant complications.
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31
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Park S, Lee J, Yang SH, Lee H, Kim JY, Park M, Kim KH, Moon JJ, Cho S, Lee S, Kim Y, Lee H, Lee JP, Jeong CW, Kwak C, Joo KW, Lim CS, Kim YS, Hwang GS, Kim DK. Comprehensive metabolomic profiling in early IgA nephropathy patients reveals urine glycine as a prognostic biomarker. J Cell Mol Med 2021; 25:5177-5190. [PMID: 33939273 PMCID: PMC8178259 DOI: 10.1111/jcmm.16520] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 12/18/2022] Open
Abstract
Identification of a urinary metabolite biomarker with diagnostic or prognostic significance for early immunoglobulin A nephropathy (IgAN) is needed. We performed nuclear magnetic resonance‐based metabolomic profiling and identified 26 metabolites in urine samples. We collected urine samples from 201, 77, 47, 36 and 136 patients with IgAN, patients with membranous nephropathy, patients with minimal change disease, patients with lupus nephritis and healthy controls, respectively. We determined whether a metabolite level is associated with the prognosis of IgAN through Cox regression and continuous net reclassification improvement (cNRI). Finally, in vitro experiments with human kidney tubular epithelial cells (hTECs) were performed for experimental validation. As the results, the urinary glycine level was higher in the IgAN group than the control groups. A higher urinary glycine level was associated with lower risk of eGFR 30% decline in IgAN patients. The addition of glycine to a predictive model including clinicopathologic information significantly improved the predictive power for the prognosis of IgAN [cNRI 0.72 (0.28‐0.82)]. In hTECs, the addition of glycine ameliorated inflammatory signals induced by tumour necrosis factor‐α. Our study demonstrates that urinary glycine may have diagnostic and prognostic value for IgAN and indicates that urinary glycine is a protective biomarker for IgAN.
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Affiliation(s)
- Sehoon Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Armed Forces Capital Hospital, Gyeonggi-do, Korea
| | - Jueun Lee
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Korea
| | - Seung Hee Yang
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Hajeong Lee
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Korea
| | - Joo Young Kim
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Minkyoung Park
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Kyu Hong Kim
- Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Jong Joo Moon
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Semin Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Soojin Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Pyo Lee
- Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Chang Wook Jeong
- Department of Urology, Seoul National University Hospital, Seoul, Korea
| | - Cheol Kwak
- Department of Urology, Seoul National University Hospital, Seoul, Korea
| | - Kwon Wook Joo
- Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Chun Soo Lim
- Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yon Su Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Geum-Sook Hwang
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Korea.,Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Korea
| | - Dong Ki Kim
- Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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Belkadi A, Thareja G, Dadhania D, Lee JR, Muthukumar T, Snopkowski C, Li C, Halama A, Abdelkader S, Abdulla S, Mahmoud Y, Malek J, Suthanthiran M, Suhre K. Deep sequencing of DNA from urine of kidney allograft recipients to estimate donor/recipient-specific DNA fractions. PLoS One 2021; 16:e0249930. [PMID: 33857204 PMCID: PMC8049329 DOI: 10.1371/journal.pone.0249930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/27/2021] [Indexed: 11/19/2022] Open
Abstract
Kidney transplantation is the treatment of choice for patients with end-stage kidney failure, but transplanted allograft could be affected by viral and bacterial infections and by immune rejection. The standard test for the diagnosis of acute pathologies in kidney transplants is kidney biopsy. However, noninvasive tests would be desirable. Various methods using different techniques have been developed by the transplantation community. But these methods require improvements. We present here a cost-effective method for kidney rejection diagnosis that estimates donor/recipient-specific DNA fraction in recipient urine by sequencing urinary cell DNA. We hypothesized that in the no-pathology stage, the largest tissue types present in recipient urine are donor kidney cells, and in case of rejection, a larger number of recipient immune cells would be observed. Extensive in-silico simulation was used to tune the sequencing parameters: number of variants and depth of coverage. Sequencing of DNA mixture from 2 healthy individuals showed the method is highly predictive (maximum error < 0.04). We then demonstrated the insignificant impact of familial relationship and ethnicity using an in-house and public database. Lastly, we performed deep DNA sequencing of urinary cell pellets from 32 biopsy-matched samples representing two pathology groups: acute rejection (AR, 11 samples) and acute tubular injury (ATI, 12 samples) and 9 samples with no pathology. We found a significant association between the donor/recipient-specific DNA fraction in the two pathology groups compared to no pathology (P = 0.0064 for AR and P = 0.026 for ATI). We conclude that deep DNA sequencing of urinary cells from kidney allograft recipients offers a noninvasive means of diagnosing acute pathologies in the human kidney allograft.
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Affiliation(s)
- Aziz Belkadi
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Gaurav Thareja
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Darshana Dadhania
- Department of Transplantation Medicine, New-York Presbyterian Hospital-Weill Cornell Medicine, New York, United States of America
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, United States of America
| | - John R. Lee
- Department of Transplantation Medicine, New-York Presbyterian Hospital-Weill Cornell Medicine, New York, United States of America
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, United States of America
| | - Thangamani Muthukumar
- Department of Transplantation Medicine, New-York Presbyterian Hospital-Weill Cornell Medicine, New York, United States of America
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, United States of America
| | - Catherine Snopkowski
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, United States of America
| | - Carol Li
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, United States of America
| | - Anna Halama
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Sara Abdelkader
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Silvana Abdulla
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Yasmin Mahmoud
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Joel Malek
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
| | - Manikkam Suthanthiran
- Department of Transplantation Medicine, New-York Presbyterian Hospital-Weill Cornell Medicine, New York, United States of America
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, United States of America
| | - Karsten Suhre
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
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Tinel C, Anglicheau D. [Urinary biomarkers in kidney transplant recipients: From technological innovations to clinical development]. Nephrol Ther 2021; 17S:S83-S87. [PMID: 33910704 DOI: 10.1016/j.nephro.2020.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 03/01/2020] [Indexed: 11/16/2022]
Abstract
In kidney transplantation, the assessment of individual risks remains highly imperfect and highlights the need for robust noninvasive biomarkers with the overall goal to improve patient and graft outcomes. In the field of noninvasive biomarkers discovery, urinary biomarkers are promising tools which use easily accessible biological fluid. During the past decades, the technical revolution in the fields of genetics and molecular biology, and advances in chemistry and data analysis have led to a wealth of studies using urinary cell pellets or supernatants from kidney transplant recipients. Transcriptomic, proteomic and metabonomic analyses have suggested numerous signatures for the diagnoses of acute rejection, delayed-graft function or interstitial fibrosis. Nevertheless, the translation and validation of exploratory findings and their implementation into standard clinical practice remain challenging. This requires dedicated prospective interventional trials demonstrating that the use of these biomarkers avoids invasive procedures and improves patient or transplant outcomes.
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Affiliation(s)
- Claire Tinel
- Service de néphrologie et transplantation rénale, Assistance publique-Hôpitaux de Paris, 149, rue de Sèvres, 75015 Paris, France; Faculte de médecine Necker, Institut Necker-Enfants-Malades, 156-160, rue de Vaugirard, 75015 Paris, France; Inserm, U1151, 156-160, rue de Vaugirard, 75015 Paris, France.
| | - Dany Anglicheau
- Service de néphrologie et transplantation rénale, Assistance publique-Hôpitaux de Paris, 149, rue de Sèvres, 75015 Paris, France; Faculte de médecine Necker, Institut Necker-Enfants-Malades, 156-160, rue de Vaugirard, 75015 Paris, France; Inserm, U1151, 156-160, rue de Vaugirard, 75015 Paris, France
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Sigdel TK, Schroeder AW, Yang JYC, Sarwal RD, Liberto JM, Sarwal MM. Targeted Urine Metabolomics for Monitoring Renal Allograft Injury and Immunosuppression in Pediatric Patients. J Clin Med 2020; 9:jcm9082341. [PMID: 32707952 PMCID: PMC7465632 DOI: 10.3390/jcm9082341] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/15/2020] [Accepted: 07/21/2020] [Indexed: 12/13/2022] Open
Abstract
Despite new advancements in surgical tools and therapies, exposure to immunosuppressive drugs related to non-immune and immune injuries can cause slow deterioration and premature failure of organ transplants. Diagnosis of these injuries by non-invasive urine monitoring would be a significant clinical advancement for patient management, especially in pediatric cohorts. We investigated the metabolomic profiles of biopsy matched urine samples from 310 unique kidney transplant recipients using gas chromatography-mass spectrometry (GC-MS). Focused metabolite panels were identified that could detect biopsy confirmed acute rejection with 92.9% sensitivity and 96.3% specificity (11 metabolites) and could differentiate BK viral nephritis (BKVN) from acute rejection with 88.9% sensitivity and 94.8% specificity (4 metabolites). Overall, targeted metabolomic analyses of biopsy-matched urine samples enabled the generation of refined metabolite panels that non-invasively detect graft injury phenotypes with high confidence. These urine biomarkers can be rapidly assessed for non-invasive diagnosis of specific transplant injuries, opening the window for precision transplant medicine.
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Altered Metabolome of Lipids and Amino Acids Species: A Source of Early Signature Biomarkers of T2DM. J Clin Med 2020; 9:jcm9072257. [PMID: 32708684 PMCID: PMC7409008 DOI: 10.3390/jcm9072257] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/12/2020] [Accepted: 07/14/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus, a disease of modern civilization, is considered the major mainstay of mortalities around the globe. A great number of biochemical changes have been proposed to occur at metabolic levels between perturbed glucose, amino acid, and lipid metabolism to finally diagnoe diabetes mellitus. This window period, which varies from person to person, provides us with a unique opportunity for early detection, delaying, deferral and even prevention of diabetes. The early detection of hyperglycemia and dyslipidemia is based upon the detection and identification of biomarkers originating from perturbed glucose, amino acid, and lipid metabolism. The emerging “OMICS” technologies, such as metabolomics coupled with statistical and bioinformatics tools, proved to be quite useful to study changes in physiological and biochemical processes at the metabolic level prior to an eventual diagnosis of DM. Approximately 300–400 such metabolites have been reported in the literature and are considered as predicting or risk factor-reporting metabolic biomarkers for this metabolic disorder. Most of these metabolites belong to major classes of lipids, amino acids and glucose. Therefore, this review represents a snapshot of these perturbed plasma/serum/urinary metabolic biomarkers showing a significant correlation with the future onset of diabetes and providing a foundation for novel early diagnosis and monitoring the progress of metabolic syndrome at early symptomatic stages. As most metabolites also find their origin from gut microflora, metabolism and composition of gut microflora also vary between healthy and diabetic persons, so we also summarize the early changes in the gut microbiome which can be used for the early diagnosis of diabetes.
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Abstract
Enzyme activity may be more pathophysiologically relevant than enzyme quantity and is regulated by changes in conformational status that are undetectable by traditional proteomic approaches. Further, enzyme activity may provide insights into rapid physiological responses to inflammation/injury that are not dependent on de novo protein transcription. Activity-based protein profiling (ABPP) is a chemical proteomic approach designed to characterize and identify active enzymes within complex biological samples. Activity probes have been developed to interrogate multiple enzyme families with broad applicability, including but not limited to serine hydrolases, cysteine proteases, matrix metalloproteases, nitrilases, caspases, and histone deacetylases. The goal of this overview is to describe the overall rationale, approach, methods, challenges, and potential applications of ABPP to transplantation research. To do so, we present a case example of urine serine hydrolase ABPP in kidney transplant rejection to illustrate the utility and workflow of this analytical approach. Ultimately, developing novel transplant therapeutics is critically dependent on understanding the pathophysiological processes that result in loss of transplant function. ABPP offers a new dimension for characterizing dynamic changes in clinical samples. The capacity to identify and measure relevant enzyme activities provides fresh opportunities for understanding these processes and may help identify markers of disease activity for the development of novel diagnostics and real-time monitoring of patients. Finally, these insights into enzyme activity may also help to identify new transplant therapeutics, such as enzyme-specific inhibitors.
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Gerges-Knafl D, Pichler P, Zimprich A, Hotzy C, Barousch W, Lang RM, Lobmeyr E, Baumgartner-Parzer S, Wagner L, Winnicki W. The urinary microbiome shows different bacterial genera in renal transplant recipients and non-transplant patients at time of acute kidney injury - a pilot study. BMC Nephrol 2020; 21:117. [PMID: 32252662 PMCID: PMC7133001 DOI: 10.1186/s12882-020-01773-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Background In the past urine was considered sterile. Through the introduction of next generation sequencing, it has become clear that a urinary microbiome exists. Acute kidney injury (AKI) represents a major threat to kidney transplant recipients. Remarkable changes in the urinary metabolome occur during AKI, which may influence the urinary microbiome. To our knowledge, this is the first study that examines the urinary microbiome in renal transplant recipients (RTX) and non-transplant recipients (nRTX) at time of AKI. Methods In this cross-sectional pilot-study the urinary microbiome of 21 RTX and 9 nRTX with AKI was examined. Clean catch morning urine samples were obtained from all patients on the first day of AKI diagnosis. AKI was defined according to KDIGO guidelines. Urinary microbiota and the urinary metabolome during AKI were assessed in one patient. 16S rRNA sequencing was performed. Sequences were processed using UPARSE-pipeline for operational taxonomic units (OTU) and taxon finding. Results We successfully extracted and sequenced bacterial DNA from 100% of the urine samples. All 30 patients revealed at least 106,138 reads. 319 OTU and 211 different genera were identified. The microbiotic diversity richness in the RTX group was no different from the nRTX group. Eighteen genera were solely present in nRTX and 7 in RTX. Conclusions The urinary microbiome at time of AKI showed different bacterial genera in RTX compared to nRTX. The nRTX group exhibited no different diversity to the RTX group. Irrespective of the status of a previous renal transplantation, the urinary microbiome comprised > 210 different genera. An intraindividual change in microbiota diversity and richness was observed in one study patient during recovery from AKI.
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Affiliation(s)
- Daniela Gerges-Knafl
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
| | - Peter Pichler
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | | | - Christoph Hotzy
- Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Barousch
- Department of Laboratory Medicine, Division of Clinical Microbiology, Medical University of Vienna, Vienna, Austria
| | - Rita M Lang
- Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Lobmeyr
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - Sabina Baumgartner-Parzer
- Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Ludwig Wagner
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Wolfgang Winnicki
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
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Metabolomic biomarkers are associated with mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Future Sci OA 2019; 6:FSO441. [PMID: 32025330 PMCID: PMC6997913 DOI: 10.2144/fsoa-2019-0124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Aim: To assess the ability of signature metabolites alone, or in combination with the model for end-stage liver disease-Na (MELD-Na) score to predict mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Materials & methods: Plasma metabolites were detected using ultrahigh-performance liquid chromatography/tandem mass spectrometry in 39 patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Mortality was predicted using Cox proportional hazards regression and time-dependent receiver operating characteristic curve analyses. Results: The top five metabolites with significantly greater accuracy than the MELD-Na score (area under the receiver operating characteristic curve [AUROC] = 0.7591) to predict 1-year mortality were myo-inositol (AUROC = 0.9537), N-acetylputrescine (AUROC = 0.9018), trans-aconitate (AUROC = 0.8880), erythronate (AUROC = 0.8345) and N6-carbamoylthreonyladenosine (AUROC = 0.8055). Several combined MELD-Na-metabolite models increased the accuracy of predicted 1-year mortality substantially (AUROC increased from 0.7591 up to 0.9392). Conclusion: Plasma metabolites have the potential to enhance the accuracy of mortality predictions, minimize underestimates of mortality in patients with cirrhosis and low MELD-Na scores, and promote equitable allocation of donor livers. To receive a liver transplant, patients with cirrhosis need to be listed on the US liver transplant waiting list based on a score called the model for end-stage liver disease-Na (MELD-Na) score that is expected to accurately rank the patients based on urgency for a liver transplant. However, MELD-Na score is not sufficiently accurate to identify many patients with cirrhosis with the highest urgency, and this results in longer waiting times on the liver transplant list, and therefore higher death rates. We identified several metabolomic biomarkers that can increase the accuracy of the MELD-Na score, and optimize the allocation of donor livers for transplantation of patients with cirrhosis.
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A urinary metabolite constellation to detect acute rejection in kidney allografts. EBioMedicine 2019; 48:505-512. [PMID: 31648995 PMCID: PMC6838399 DOI: 10.1016/j.ebiom.2019.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 10/04/2019] [Accepted: 10/04/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND To validate a novel method for post-transplant surveillance to detect kidney allograft rejection via a characteristic constellation of the urine metabolites alanine, citrate, lactate, and urea investigated by nuclear magnetic resonance (NMR) spectroscopy a first prospective, observational study was performed. METHODS Within the UMBRELLA study 986 urine specimens were collected from 109 consecutively enrolled renal transplant recipients, and metabolite constellations were analyzed. A metabolite rejection score was calculated and compared to histopathological results of corresponding indication and protocol allograft biopsies (n = 206). FINDINGS The metabolite constellation was found to be a useful biomarker to non-invasively detect acute allograft rejection (AUC = 0.75; 95% confidence interval (CI) 0.68-0.83; based on 46 cases and 520 control samples). Combined analysis of the metabolite rejection score and the estimated glomerular filtration rate (eGFR) at the time of urine sampling further improved the overall test performance significantly (AUC = 0.84; 95% CI 0.76-0.91; based on 42 cases and 468 controls). Regarding the time course analysis in patients without rejection episodes the test results remained well below a diagnostic threshold associated with high risk of acute rejection. In other cases, a marked increase above this threshold indicated acute allograft rejection already six to ten days before diagnostic renal biopsies were performed. INTERPRETATION A combination of an NMR-based urine metabolite analysis and eGFR is promising as a non-invasive test for post-transplant surveillance and to support decision making whether renal allografts need histopathological evaluation.
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Wang Z, Lyu Z, Pan L, Zeng G, Randhawa P. Defining housekeeping genes suitable for RNA-seq analysis of the human allograft kidney biopsy tissue. BMC Med Genomics 2019; 12:86. [PMID: 31208411 PMCID: PMC6580566 DOI: 10.1186/s12920-019-0538-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 05/24/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND RNA-seq is poised to play a major role in the management of kidney transplant patients. Rigorous definition of housekeeping genes (HKG) is essential for further progress in this field. Using single genes or a limited set HKG is inherently problematic since their expression might be altered by specific diseases in the patients being studied. METHODS To generate a HKG set specific for kidney transplantation, we performed RNA-sequencing from renal allograft biopsies collected in a variety of clinical settings. Various normalization methods were applied to identify transcripts that had a coefficient of variation of expression that was below the 2nd percentile across all samples, and the corresponding genes were designated as housekeeping genes. Comparison with transcriptomic data from the Gene Expression Omnibus (GEO) database, pathway analysis and molecular biological functions were utilized to validate the housekeeping genes set. RESULTS We have developed a bioinformatics solution to this problem by using nine different normalization methods to derive large HKG gene sets from a RNA-seq data set of 47,611 transcripts derived from 30 biopsies. These biopsies were collected in a variety of clinical settings, including normal function, acute rejection, interstitial nephritis, interstitial fibrosis/tubular atrophy and polyomavirus nephropathy. Transcripts with coefficient of variation below the 2nd percentile were designated as HKG, and validated by showing their virtual absence in diseased allograft derived transcriptomic data sets available in the GEO. Pathway analysis indicated a role for these genes in maintenance of cell morphology, pyrimidine metabolism, and intracellular protein signaling. CONCLUSIONS Utilization of these objectively defined HKG data sets will guard against errors resulting from focusing on individual genes like 18S RNA, actin & tubulin, which do not maintain constant expression across the known spectrum of renal allograft pathology.
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Affiliation(s)
- Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
| | - Zili Lyu
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Ling Pan
- Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Gang Zeng
- Department of Pathology, University of Pittsburgh Medical Center, E737 UPMC-Montefiore Hospital, 3459 Fifth Ave, Pittsburgh, PA 15213 USA
| | - Parmjeet Randhawa
- Department of Pathology, University of Pittsburgh Medical Center, E737 UPMC-Montefiore Hospital, 3459 Fifth Ave, Pittsburgh, PA 15213 USA
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Archdekin B, Sharma A, Gibson IW, Rush D, Wishart DS, Blydt-Hansen TD. Non-invasive differentiation of non-rejection kidney injury from acute rejection in pediatric renal transplant recipients. Pediatr Transplant 2019; 23:e13364. [PMID: 30719822 DOI: 10.1111/petr.13364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 12/11/2018] [Accepted: 12/21/2018] [Indexed: 12/19/2022]
Abstract
Acute kidney injury (AKI) is a major concern in pediatric kidney transplant recipients, where non-alloimmune causes must be distinguished from rejection. We sought to identify a urinary metabolite signature associated with non-rejection kidney injury (NRKI) in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant participants were obtained at time of kidney biopsy and quantitatively assayed for 133 metabolites by mass spectrometry. Metabolite profiles were analyzed via projection on latent structures discriminant analysis. Mixed-effects regression identified laboratory and clinical predictors of NRKI and distinguished NRKI from T cell-mediated rejection (CMR), antibody-mediated rejection (AMR), and mixed CMR/AMR. Urine samples (n = 199) without rejection were split into NRKI (n = 26; ΔSCr ≥25%), pre-NRKI (n = 35; ΔSCr ≥10% and <25%), and no NRKI (n = 138; ΔSCr <10%) groups. The NRKI discriminant score (dscore) distinguished between NRKI and no NRKI (AUC = 0.86; 95% CI = 0.79-0.94), confirmed by leave-one-out cross-validation (AUC = 0.79; 95% CI = 0.68-0.89). The NRKI dscore also distinguished between NRKI and pre-NRKI (AUC = 0.82; 95% CI = 0.71-0.93). In a linear mixed-effects regression model to account for repeated measures, the NRKI dscore was independent of concurrent rejection, but there was a non-statistical trend for higher dscores with rejection severity. A second exploratory classifier developed to distinguish NRKI from clinical rejection had similar test characteristics (AUC = 0.81, 95% CI = 0.70-0.92, confirmed by LOOCV). This study demonstrates the potential of a urine metabolite classifier to detect NRKI in pediatric kidney transplant patients and non-invasively discriminate NRKI from rejection.
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Affiliation(s)
- Ben Archdekin
- Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Atul Sharma
- Department of Pediatrics and Child Health, Children's Hospital at Health Sciences Center, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ian W Gibson
- Department of Pathology, Health Sciences Center, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David Rush
- Department of Medicine, Health Sciences Center, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David S Wishart
- The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada
| | - Tom D Blydt-Hansen
- Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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Chen J, Bhattacharya S, Sirota M, Laiudompitak S, Schaefer H, Thomson E, Wiser J, Sarwal MM, Butte AJ. Assessment of Postdonation Outcomes in US Living Kidney Donors Using Publicly Available Data Sets. JAMA Netw Open 2019; 2:e191851. [PMID: 30977847 PMCID: PMC6481454 DOI: 10.1001/jamanetworkopen.2019.1851] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 02/12/2019] [Indexed: 12/30/2022] Open
Abstract
Importance There are limited resources providing postdonation conditions that can occur in living donors (LDs) of solid-organ transplant. Consequently, it is difficult to visualize and understand possible postdonation outcomes in LDs. Objective To assemble an open access resource that is representative of the demographic characteristics in the US national registry, maintained by the Organ Procurement and Transplantation Network and administered by the United Network for Organ Sharing, but contains more follow-up information to help to examine postdonation outcomes in LDs. Design, Setting, and Participants Cohort study in which the data for the resource and analyses stemmed from the transplant data set derived from 27 clinical studies from the ImmPort database, which is an open access repository for clinical studies. The studies included data collected from 1963 to 2016. Data from the United Network for Organ Sharing Organ Procurement and Transplantation Network national registry collected from October 1987 to March 2016 were used to determine representativeness. Data analysis took place from June 2016 to May 2018. Data from 20 ImmPort clinical studies (including clinical trials and observational studies) were curated, and a cohort of 11 263 LDs was studied, excluding deceased donors, LDs with 95% or more missing data, and studies without a complete data dictionary. The harmonization process involved the extraction of common features from each clinical study based on categories that included demographic characteristics as well as predonation and postdonation data. Main Outcomes and Measures Thirty-six postdonation events were identified, represented, and analyzed via a trajectory network analysis. Results The curated data contained 10 869 living kidney donors (median [interquartile range] age, 39 [31-48] years; 6175 [56.8%] women; and 9133 [86.6%] of European descent). A total of 9558 living kidney donors with postdonation data were analyzed. Overall, 1406 LDs (14.7%) had postdonation events. The 4 most common events were hypertension (806 [8.4%]), diabetes (190 [2.0%]), proteinuria (171 [1.8%]), and postoperative ileus (147 [1.5%]). Relatively few events (n = 269) occurred before the 2-year postdonation mark. Of the 1746 events that took place 2 years or more after donation, 1575 (90.2%) were nonsurgical; nonsurgical conditions tended to occur in the wide range of 2 to 40 years after donation (odds ratio, 38.3; 95% CI, 4.12-1956.9). Conclusions and Relevance Most events that occurred more than 2 years after donation were nonsurgical and could occur up to 40 years after donation. Findings support the construction of a national registry for long-term monitoring of LDs and confirm the value of secondary reanalysis of clinical studies.
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Affiliation(s)
- Jieming Chen
- Bakar Computational Health Sciences Institute, University of California, San Francisco
- Department of Pediatrics, University of California, San Francisco
- Now with the Department of Bioinformatics and Computational Biology, Genentech, Inc, South San Francisco, California
| | - Sanchita Bhattacharya
- Bakar Computational Health Sciences Institute, University of California, San Francisco
- Department of Pediatrics, University of California, San Francisco
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, University of California, San Francisco
- Department of Pediatrics, University of California, San Francisco
| | - Sunisa Laiudompitak
- Bakar Computational Health Sciences Institute, University of California, San Francisco
| | | | | | - Jeff Wiser
- Northrop Grumman Information Systems Health IT, Rockville, Maryland
| | - Minnie M. Sarwal
- Department of Pediatrics, University of California, San Francisco
- Division of MultiOrgan Transplant, Department of Surgery and Medicine, University of California, San Francisco
| | - Atul J. Butte
- Bakar Computational Health Sciences Institute, University of California, San Francisco
- Department of Pediatrics, University of California, San Francisco
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Abbiss H, Maker GL, Trengove RD. Metabolomics Approaches for the Diagnosis and Understanding of Kidney Diseases. Metabolites 2019; 9:E34. [PMID: 30769897 PMCID: PMC6410198 DOI: 10.3390/metabo9020034] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/29/2019] [Accepted: 02/05/2019] [Indexed: 02/07/2023] Open
Abstract
Diseases of the kidney are difficult to diagnose and treat. This review summarises the definition, cause, epidemiology and treatment of some of these diseases including chronic kidney disease, diabetic nephropathy, acute kidney injury, kidney cancer, kidney transplantation and polycystic kidney diseases. Numerous studies have adopted a metabolomics approach to uncover new small molecule biomarkers of kidney diseases to improve specificity and sensitivity of diagnosis and to uncover biochemical mechanisms that may elucidate the cause and progression of these diseases. This work includes a description of mass spectrometry-based metabolomics approaches, including some of the currently available tools, and emphasises findings from metabolomics studies of kidney diseases. We have included a varied selection of studies (disease, model, sample number, analytical platform) and focused on metabolites which were commonly reported as discriminating features between kidney disease and a control. These metabolites are likely to be robust indicators of kidney disease processes, and therefore potential biomarkers, warranting further investigation.
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Affiliation(s)
- Hayley Abbiss
- School of Veterinary and Life Sciences, Murdoch University, 90 South Street, Perth 6150, Australia.
- Separation Science and Metabolomics Laboratory, Murdoch University, 90 South Street, Perth 6150, Australia.
| | - Garth L Maker
- School of Veterinary and Life Sciences, Murdoch University, 90 South Street, Perth 6150, Australia.
- Separation Science and Metabolomics Laboratory, Murdoch University, 90 South Street, Perth 6150, Australia.
| | - Robert D Trengove
- Separation Science and Metabolomics Laboratory, Murdoch University, 90 South Street, Perth 6150, Australia.
- Metabolomics Australia, Murdoch University Node, Murdoch University, 90 South Street, Perth 6150, Australia.
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Manzia TM, Gazia C, Baiocchi L, Lenci I, Milana M, Santopaolo F, Angelico R, Tisone G. Clinical Operational Tolerance and Immunosuppression Minimization in Kidney Transplantation: Where Do We Stand? Rev Recent Clin Trials 2019; 14:189-202. [PMID: 30868959 DOI: 10.2174/1574887114666190313170205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 02/27/2019] [Accepted: 03/05/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND The 20th century represents a breakthrough in the transplantation era, since the first kidney transplantation between identical twins was performed. This was the first case of tolerance, since the recipient did not need immunosuppression. However, as transplantation became possible, an immunosuppression-free status became the ultimate goal, since the first tolerance case was a clear exception from the hard reality nowadays represented by rejection. METHODS A plethora of studies was described over the past decades to understand the molecular mechanisms responsible for rejection. This review focuses on the most relevant studies found in the literature where renal tolerance cases are claimed. Contrasting, and at the same time, encouraging outcomes are herein discussed and a glimpse on the main renal biomarkers analyzed in this field is provided. RESULTS The activation of the immune system has been shown to play a central role in organ failure, but also it seems to induce a tolerance status when an allograft is performed, despite tolerance is still rare to register. Although there are still overwhelming challenges to overcome and various immune pathways remain arcane; the immunosuppression minimization might be more attainable than previously believed. CONCLUSION . Multiple biomarkers and tolerance mechanisms suspected to be involved in renal transplantation have been investigated to understand their real role, with still no clear answers on the topic. Thus, the actual knowledge provided necessarily leads to more in-depth investigations, although many questions in the past have been answered, there are still many issues on renal tolerance that need to be addressed.
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Affiliation(s)
- Tommaso Maria Manzia
- Transplant and Hepatobiliary Unit, Department of Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Gazia
- Transplant and Hepatobiliary Unit, Department of Surgery, University of Rome Tor Vergata, Rome, Italy
- Department of Surgery, Abdominal Organ Transplant Program, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
- Wake Forest Institute for Regenerative Medicine, Department of Surgery, Winston-Salem, NC, United States
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome, Italy
| | - Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome, Italy
| | | | - Roberta Angelico
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Giuseppe Tisone
- Transplant and Hepatobiliary Unit, Department of Surgery, University of Rome Tor Vergata, Rome, Italy
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Rhee EP, Waikar SS, Rebholz CM, Zheng Z, Perichon R, Clish CB, Evans AM, Avila J, Denburg MR, Anderson AH, Vasan RS, Feldman HI, Kimmel PL, Coresh J. Variability of Two Metabolomic Platforms in CKD. Clin J Am Soc Nephrol 2018; 14:40-48. [PMID: 30573658 PMCID: PMC6364529 DOI: 10.2215/cjn.07070618] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 10/15/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND OBJECTIVES Nontargeted metabolomics can measure thousands of low-molecular-weight biochemicals, but important gaps limit its utility for biomarker discovery in CKD. These include the need to characterize technical and intraperson analyte variation, to pool data across platforms, and to outline analyte relationships with eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Plasma samples from 49 individuals with CKD (eGFR<60 ml/min per 1.73 m2 and/or ≥1 g proteinuria) were examined from two study visits; 20 samples were repeated as blind replicates. To enable comparison across two nontargeted platforms, samples were profiled at Metabolon and the Broad Institute. RESULTS The Metabolon platform reported 837 known metabolites and 483 unnamed compounds (selected from 44,953 unknown ion features). The Broad Institute platform reported 594 known metabolites and 26,106 unknown ion features. Median coefficients of variation (CVs) across blind replicates were 14.6% (Metabolon) and 6.3% (Broad Institute) for known metabolites, and 18.9% for (Metabolon) unnamed compounds and 24.5% for (Broad Institute) unknown ion features. Median CVs for day-to-day variability were 29.0% (Metabolon) and 24.9% (Broad Institute) for known metabolites, and 41.8% for (Metabolon) unnamed compounds and 40.9% for (Broad Institute) unknown ion features. A total of 381 known metabolites were shared across platforms (median correlation 0.89). Many metabolites were negatively correlated with eGFR at P<0.05, including 35.7% (Metabolon) and 18.9% (Broad Institute) of known metabolites. CONCLUSIONS Nontargeted metabolomics quantifies >1000 analytes with low technical CVs, and agreement for overlapping metabolites across two leading platforms is excellent. Many metabolites demonstrate substantial intraperson variation and correlation with eGFR.
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Affiliation(s)
- Eugene P Rhee
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts;
| | - Sushrut S Waikar
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Casey M Rebholz
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Zihe Zheng
- Department of Biostatistics, Epidemiology, and Informatics
| | | | - Clary B Clish
- Metabolite Profiling, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | - Julian Avila
- Metabolite Profiling, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | | | - Ramachandran S Vasan
- Sections of Preventive Medicine and Epidemiology and Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; and
| | - Harold I Feldman
- Department of Biostatistics, Epidemiology, and Informatics.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Paul L Kimmel
- Division of Kidney Urologic and Hematologic Diseases, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Josef Coresh
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland; .,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Landsberg A, Sharma A, Gibson IW, Rush D, Wishart DS, Blydt-Hansen TD. Non-invasive staging of chronic kidney allograft damage using urine metabolomic profiling. Pediatr Transplant 2018; 22:e13226. [PMID: 29855144 DOI: 10.1111/petr.13226] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/18/2018] [Indexed: 01/06/2023]
Abstract
Chronic kidney allograft damage is characterized by IFTA and GS. We sought to identify urinary metabolite signatures associated with severity of IFTA and GS in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant recipients were obtained at the time of kidney biopsy and assayed for 133 metabolites by mass spectrometry. Metabolite profiles were quantified via PLS-DA. We used mixed-effects regression to identify laboratory and clinical predictors of histopathology. Urine samples (n = 174) without rejection or AKI were divided into training/validation sets (75:25%). Metabolite classifiers trained on IFTA severity and %GS showed strong statistical correlation (r = .73, P < .001 and r = .72; P < .001, respectively) and remained significant on the validation sets. Regression analysis identified additional clinical features that improved prediction: months post-transplant (GS, IFTA); and proteinuria, GFR, and age (GS only). Addition of clinical variables improved performance of the %GS classifier (AUC = 0.9; 95% CI = 0.85-0.96) but not for IFTA (AUC = 0.82; 95% CI = 0.71-0.92). Despite the presence of potentially confounding phenotypes, these findings were further validated in samples withheld for rejection or AKI. We identify urine metabolite classifiers for IFTA and GS, which may prove useful for non-invasive assessment of histopathological damage.
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Affiliation(s)
- Adina Landsberg
- Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Atul Sharma
- Department of Pediatrics and Child Health, Children's Hospital at Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada
| | - Ian W Gibson
- Department of Pathology, Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada
| | - David Rush
- Department of Medicine, Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada
| | - David S Wishart
- The Metabolomics Innovation Center, University of Alberta, Edmonton, AB, Canada
| | - Tom D Blydt-Hansen
- Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada
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Wiebe C, Ho J, Gibson IW, Rush DN, Nickerson PW. Carpe diem-Time to transition from empiric to precision medicine in kidney transplantation. Am J Transplant 2018; 18:1615-1625. [PMID: 29603637 DOI: 10.1111/ajt.14746] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/13/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023]
Abstract
The current immunosuppressive pipeline in kidney transplantation is limited. In part, this is due to excellent one-year allograft outcomes with the current standard of care (ie, calcineurin inhibitor in combination with anti-proliferative agents). Despite this success, a recent Federal government-sponsored systematic review has identified gaps/limits in the evidence of what constitutes optimal calcineurin inhibitor use in the short- and long-term. Moreover, recent empiric approaches to minimize/withdraw/convert from calcineurin inhibitors have come with the price of increased alloreactivity. As the time horizon to replace calcineurin inhibitors on a global scale may be distant, the transplant community should seize the opportunity to develop ways to personalize calcineurin inhibitor immunosuppression to the individual-transitioning from empiricism to precision. The authors argue in this viewpoint that the path to precision will require measures capable of detecting subclinical alloreactivity to define adequacy of immunosuppression, as well as novel genetic analytics to accurately define alloimmune risk at the individual level-both approaches will require validation in clinical trials.
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Affiliation(s)
- Chris Wiebe
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.,Diagnostic Services of Manitoba, Winnipeg, MB, Canada
| | - Julie Ho
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.,Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Ian W Gibson
- Diagnostic Services of Manitoba, Winnipeg, MB, Canada.,Department of Pathology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - David N Rush
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Peter W Nickerson
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.,Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.,Diagnostic Services of Manitoba, Winnipeg, MB, Canada
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48
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Urine biomarkers informative of human kidney allograft rejection and tolerance. Hum Immunol 2018; 79:343-355. [DOI: 10.1016/j.humimm.2018.01.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/16/2018] [Accepted: 01/16/2018] [Indexed: 12/15/2022]
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Mindikoglu AL, Opekun AR, Putluri N, Devaraj S, Sheikh-Hamad D, Vierling JM, Goss JA, Rana A, Sood GK, Jalal PK, Inker LA, Mohney RP, Tighiouart H, Christenson RH, Dowling TC, Weir MR, Seliger SL, Hutson WR, Howell CD, Raufman JP, Magder LS, Coarfa C. Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis. Transl Res 2018; 195:25-47. [PMID: 29291380 PMCID: PMC6037419 DOI: 10.1016/j.trsl.2017.12.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/16/2017] [Accepted: 12/04/2017] [Indexed: 02/07/2023]
Abstract
The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P <0.0001). Erythronate (R = 0.594, P <0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P <0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P <0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism.
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Affiliation(s)
- Ayse L Mindikoglu
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas; Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas.
| | - Antone R Opekun
- Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Division of Gastroenterology, Nutrition and Hepatology, Baylor College of Medicine, Houston, Texas
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Sridevi Devaraj
- Clinical Chemistry and Point of Care Technology, Texas Children's Hospital and Health Centers, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
| | - David Sheikh-Hamad
- Department of Medicine, Division of Nephrology, Baylor College of Medicine, Houston, Texas
| | - John M Vierling
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas; Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - John A Goss
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas
| | - Abbas Rana
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas
| | - Gagan K Sood
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas
| | - Prasun K Jalal
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas
| | - Lesley A Inker
- Department of Medicine, Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | | | - Hocine Tighiouart
- Institute for Clinical Research and Health Policy Studies, Biostatistics, Epidemiology and Research Design (BERD) Center, Tufts University School of Medicine, Boston, Massachusetts
| | - Robert H Christenson
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Thomas C Dowling
- Ferris State University, College of Pharmacy, Grand Rapids, Michigan
| | - Matthew R Weir
- Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Stephen L Seliger
- Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland
| | - William R Hutson
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Charles D Howell
- Department of Medicine, Howard University College of Medicine, Washington, District of Columbia
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Laurence S Magder
- Department of Epidemiology and Public Health, Division of Biostatistics and Bioinformatics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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Plasma Exosomes From HLA-Sensitized Kidney Transplant Recipients Contain mRNA Transcripts Which Predict Development of Antibody-Mediated Rejection. Transplantation 2017; 101:2419-2428. [PMID: 28557957 DOI: 10.1097/tp.0000000000001834] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Sensitization to HLA remains a significant immunologic barrier to successful transplantation. Identifying immune mechanisms responsible for antibody-mediated rejection (AMR) is an important goal. Here, we explored the possibility of predicting the risk for AMR by measuring mRNA transcripts of AMR-associated genes in plasma exosomes from kidney transplant patients. METHODS Total RNA was extracted from exosomes purified from 152 ethylenediaminetetraacetic acid-plasma samples of 64 patients (18 AMR, 8 cell-mediated rejection [CMR], 38 no rejection in desensitized [DES] and non-DES control groups) for reverse transcription into cDNA, preamplification and then real time quantitative polymerase chain reaction (qPCR) for 21 candidate genes. The mRNA transcript levels of each gene were calculated. Comparisons were made among 4 patient groups for each gene and also for a gene combination score based on selected genes. RESULTS Among 21 candidate genes, we identified multiple genes (gp130, CCL4, TNFα, SH2D1B, CAV1, atypical chemokine receptor 1 [duffy blood group]) whose mRNA transcript levels in plasma exosomes significantly increased among AMR compared with CMR and/or control patients. A gene combination score calculated from 4 genes of gp130, SH2D1B, TNFα, and CCL4 was significantly higher in the AMR than the CMR (P < 0.0001) and no rejection control groups (P < 0.01 vs DES control, P < 0.05 vs non-DES control). CONCLUSIONS Our results suggest that plasma exosomes may contain information indicating clinical conditions of kidney transplant patients. mRNA transcript profiles based on gp130, SH2D1B, TNFα, and CCL4 in plasma exosomes may be used to predict on-going and/or imminent AMR.
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