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Article ; Online: Systems biology approaches in solid organ transplantation.

Kurian, Sunil M / Whisenant, Thomas C / Marsh, Christopher L

Current opinion in organ transplantation

2021 Volume 26, Issue 1, Page(s) 37–42

Abstract: Purpose of review: Organ transplantation research has led to the discovery of several interesting individual mechanistic pathways, molecules and potential drug targets but there are still no comprehensive studies that have addressed how these varied ... ...

Abstract	Purpose of review: Organ transplantation research has led to the discovery of several interesting individual mechanistic pathways, molecules and potential drug targets but there are still no comprehensive studies that have addressed how these varied mechanisms work in unison to regulate the posttransplant immune response that drives kidney rejection and dysfunction. Recent findings: Systems biology is a rapidly expanding field that aims to integrate existing knowledge of molecular concepts and large-scale genomic and clinical datasets into networks that can be used in cutting edge computational models to define disease mechanisms in a holistic manner. Systems biology approaches have brought a paradigm shift from a reductionist view of biology to a wider agnostic assessment of disease from several lines of evidence. Although the complex nature of the posttransplant immune response makes it difficult to pinpoint mechanisms, systems biology is enabling discovery of unknown biological interactions using the cumulative power of genomic data sets, clinical data and endpoints, and improved computational methods for the systematic deconvolution of this response. Summary: An integrative systems biology approach that leverages genomic data from varied technologies, such as DNA sequencing, copy number variation, RNA sequencing, and methylation profiles along with long-term clinical follow-up data has the potential to define a framework that can be mined to provide novel insights for developing therapeutic interventions in organ transplantation.
MeSH term(s)	DNA Copy Number Variations/immunology ; Graft Survival/physiology ; Humans ; Immunity, Humoral/immunology ; Kidney Transplantation/methods ; Systems Biology/methods ; Transplantation, Homologous
Language	English
Publishing date	2021-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1390429-2
ISSN	1531-7013 ; 1087-2418
ISSN (online)	1531-7013
ISSN	1087-2418
DOI	10.1097/MOT.0000000000000837
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Article ; Online: Toward Improved and Standardized Diagnostic Pipelines in Transplantation.

Kurian, Sunil M / Whisenant, Thomas C / Marsh, Christopher L

Transplantation

2020 Volume 105, Issue 1, Page(s) 12–13

MeSH term(s)	Biopsy/standards ; Diagnosis, Computer-Assisted/standards ; Graft Rejection/diagnosis ; Graft Rejection/genetics ; Graft Rejection/pathology ; Humans ; Machine Learning/standards ; Molecular Diagnostic Techniques/standards ; Observer Variation ; Organ Transplantation/adverse effects ; Predictive Value of Tests ; Reproducibility of Results ; Treatment Outcome ; Workflow
Language	English
Publishing date	2020-12-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000003438
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Article: Renal Function at Discharge Among Kidney Recipients Experiencing Delayed Graft Function and Its Associations With Long-term Outcomes.

Kurian, Sunil M / Stewart, Darren E / Toll, Alice / Checchi, Kyle / Case, Jamie / Marsh, Christopher L

Transplantation direct

2022 Volume 8, Issue 12, Page(s) e1414

Abstract: Delayed graft function (DGF) after kidney transplantation is associated with higher rates of acute rejection and poor graft survival and outcomes. Current DGF definitions based on posttransplant need for dialysis are not standardized and there are no ... ...

Abstract	Delayed graft function (DGF) after kidney transplantation is associated with higher rates of acute rejection and poor graft survival and outcomes. Current DGF definitions based on posttransplant need for dialysis are not standardized and there are no objective methodologies for quantifying DGF severity. Methods: Using Organ Procurement and Transplantation Network data, we examined DGF, and used recipient serum creatinine at discharge as a correlate of renal function and DGF severity (mild: <2.5 mg/dL; severe: ≥2.5 mg/dL). The associations between donor and recipient factors and DGF severity were quantified using logistic regression. We also examined the associations between DGF severity and long-term recipient outcomes, adjusting for potential confounders. Results: A predictive model using donor and recipient factors had a reasonably good ability to discriminate mild (low creatinine) versus severe (high creatinine) DGF (c-statistic of 0.70). In Cox regression, DGF and creatinine at discharge were both independently associated with long-term outcomes, yet their effects differed depending on the outcome (graft function, death-censored graft function, recipient mortality). Our findings suggest that having DGF, but with relatively good renal function (creatinine <2.5) at discharge, may be less deleterious on graft and recipient survival compared with severe, prolonged DGF, which was associated with a decreased median graft survival of ~2.6 y compared with no DGF with low creatinine at discharge. Conclusions: Our novel DGF severity stratification identified unique factors associated with DGF severity, along with DGF's association with long-term graft and patient survival. The adverse cost and outcome implications of severe DGF warrant additional investigation to improve kidney transplantation practice.
Language	English
Publishing date	2022-11-17
Publishing country	United States
Document type	Journal Article
ISSN	2373-8731
ISSN	2373-8731
DOI	10.1097/TXD.0000000000001414
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Article ; Online: Achieving tolerance modifies cancer susceptibility profiles in liver transplant recipients.

Bhat, Mamatha / Pasini, Elisa / Patel, Preya / Yu, Jeffrey / Baciu, Cristina / Kurian, Sunil M / Levitsky, Josh

Cancer medicine

2022 Volume 12, Issue 4, Page(s) 5150–5157

Abstract: Long-term survival of transplant recipients is significantly impacted by malignancy. We aimed to determine whether calcineurin inhibitor (CNI)-treated recipients converted to and weaned off molecular target of rapamycin inhibitor (mTOR-I) therapy have ... ...

Abstract	Long-term survival of transplant recipients is significantly impacted by malignancy. We aimed to determine whether calcineurin inhibitor (CNI)-treated recipients converted to and weaned off molecular target of rapamycin inhibitor (mTOR-I) therapy have favorable changes in their molecular profiles in regard to malignancy risk. We performed gene expression profiling from liver biopsy and blood (PBMC) specimens followed by network analysis of key dysregulated genes, associated diseases and disorders, molecular and cellular functions using IPA software. Twenty non-immune, non-viremic patients were included, and 8 of them achieved tolerance. Two comparisons were performed: (1) tolerance time point vs tacrolimus monotherapy and (2) tolerance time point vs sirolimus monotherapy. Upon achieving tolerance, IPA predicted significant activation of DNA damage response (p = 5.40e-04) and inhibition of DNA replication (p = 7.56e-03). Conversion from sirolimus to tolerance showed decrease in HCC (p = 1.30e-02), hepatic steatosis (p = 5.60e-02) and liver fibrosis (p = 2.91e-02) associated genes. In conclusion, this longitudinal study of patients eventually achieving tolerance reveals an evolving molecular profile associated with decreased cancer risk and improved hepatic steatosis and liver fibrosis. This provides a biological rationale for attempting conversion to mTOR-I therapy and tolerance following liver transplantation particularly in patients at higher risk of cancer incidence and progression post-transplant.
MeSH term(s)	Humans ; Immunosuppressive Agents/adverse effects ; Liver Transplantation/adverse effects ; Carcinoma, Hepatocellular/epidemiology ; Carcinoma, Hepatocellular/genetics ; Longitudinal Studies ; Leukocytes, Mononuclear ; Liver Neoplasms/epidemiology ; Liver Neoplasms/genetics ; Sirolimus ; Liver Cirrhosis ; TOR Serine-Threonine Kinases ; Graft Rejection ; Transplant Recipients
Chemical Substances	Immunosuppressive Agents ; Sirolimus (W36ZG6FT64) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-10-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.5271
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Article ; Online: DAMPs Released From Injured Renal Tubular Epithelial Cells Activate Innate Immune Signals in Healthy Renal Tubular Epithelial Cells.

DeWolf, Sean E / Kasimsetty, Sashi G / Hawkes, Alana A / Stocks, Lisa M / Kurian, Sunil M / McKay, Dianne B

Transplantation

2021 Volume 106, Issue 8, Page(s) 1589–1599

Abstract: Background: Renal ischemia-reperfusion injury (IRI) predictably causes acute kidney injury after shock and major cardiovascular procedures in all kidneys procured for transplantation. The earliest events of IRI are triggered by molecules released from ... ...

Abstract	Background: Renal ischemia-reperfusion injury (IRI) predictably causes acute kidney injury after shock and major cardiovascular procedures in all kidneys procured for transplantation. The earliest events of IRI are triggered by molecules released from injured cells, damage-associated molecular patterns (DAMPs), that bind pattern recognition receptors (PRRs) constitutively expressed on many cells within the kidney. Activation of PRR signaling leads to production of proinflammatory molecules, which incite a cascade of inflammatory events leading to acute kidney injury. Renal tubular epithelial cells (RTECs) are particularly susceptible to ischemic injury, and proximal RTEC injury is pathognomonic of renal IRI. To better understand how injured RTECs contribute to the cycle of deleterious inflammation in the setting of renal IRI, this study asked whether DAMPs released from injured RTECs induced PRR signals in healthy RTECs. Methods: Human RTECs were necrosed ex vivo to release intracellular DAMPs and resulting necrotic supernatant used to stimulate healthy RTECs, T lymphocytes, and monocytes. Results: DAMPs released from necrosed RTECs upregulated PRRs known to be associated with renal IRI and activated mitogen-activated protein kinase signaling pathways. Proinflammatory cytokines were upregulated in response to necrotic supernatant, and this upregulation was abrogated by MEK-1 inhibition. The RTEC-derived DAMPs were also potent inducers of T-cell activation/proliferation and monocyte migration. Conclusions: This is the first study to our knowledge to show that endogenous DAMPs released from injured RTECs directly activate PRR signaling in healthy RTECs. These findings provide new insights directed to therapeutics for renal IRI.
MeSH term(s)	Acute Kidney Injury ; Alarmins ; Epithelial Cells/metabolism ; Humans ; Immunity, Innate ; Kidney/metabolism ; Reperfusion Injury/metabolism
Chemical Substances	Alarmins
Language	English
Publishing date	2021-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000004038
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Article ; Online: Mitigation of radiation exposure during surgical hepatectomy after yttrium-90 radioembolization.

Decoteau, Mary A / Steuterman, Steven / Kurian, Sunil M / Case, Jamie / Lewis, Paul R / Fisher, Jonathan S / Schaffer, Randolph L / Marsh, Christopher L

Journal of radiological protection : official journal of the Society for Radiological Protection

2021 Volume 41, Issue 3

Abstract: Yttrium-90 (Y-90) radioembolization for the treatment of hepatocellular carcinoma can present safety challenges when transplanting recently treated Y-90 patients. To reduce surgeons' contact with radioactive tissue and remain within occupational dose ... ...

Abstract	Yttrium-90 (Y-90) radioembolization for the treatment of hepatocellular carcinoma can present safety challenges when transplanting recently treated Y-90 patients. To reduce surgeons' contact with radioactive tissue and remain within occupational dose limits, current guidelines recommend delaying transplants at least 14 days, if possible. We wanted to determine the level of radiation exposure to the transplant surgeon when explanting an irradiated liver before the recommended decay period. An
MeSH term(s)	Hepatectomy ; Humans ; Occupational Exposure/analysis ; Radiation Dosage ; Radiation Exposure ; Yttrium Radioisotopes/therapeutic use
Chemical Substances	Yttrium Radioisotopes ; Yttrium-90 (1K8M7UR6O1)
Language	English
Publishing date	2021-08-19
Publishing country	England
Document type	Journal Article
ZDB-ID	639411-5
ISSN	1361-6498 ; 0952-4746
ISSN (online)	1361-6498
ISSN	0952-4746
DOI	10.1088/1361-6498/ac09c0
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Article: UNOS/OPTN Data-guided Assessment of Focal Segmental Glomerulosclerosis After Kidney Transplantation and Evaluation of Immunosuppressive Protocols in a Steroid-free Center.

Kurian, Sunil M / Spierling Bagsic, Samantha R / Case, Jamie / Barrick, Bethany L / Schaffer, Randolph / Rice, James C / Marsh, Christopher L

Transplantation direct

2021 Volume 7, Issue 9, Page(s) e738

Abstract: Background: Focal segmental glomerulosclerosis (FSGS) is a common recurrent glomerulopathy associated with graft loss and patient survival after kidney transplantation (KT). However, its natural history, clinical predictors, and treatment response are ... ...

Abstract	Background: Focal segmental glomerulosclerosis (FSGS) is a common recurrent glomerulopathy associated with graft loss and patient survival after kidney transplantation (KT). However, its natural history, clinical predictors, and treatment response are still poorly understood. Steroid withdrawal regimens in KT have been associated with improvements in cardiovascular risk and patient outcomes. The Scripps Center for Organ Transplantation (SCOT) uses a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance. Methods: We assessed the impact of our protocol on FSGS disease recurrence over a 10-y period to reassess our steroid and IS protocols and to evaluate if our patient outcomes diverge from published data. We compared 4 groups: steroids always, steroid free, steroid switch on, and steroid weaned off. We used IS and induction-matched retrospective data from United Network for Organ Sharing (UNOS) to investigate patient and graft survival for FSGS at SCOT. Results: Our analysis results differ from earlier studies showing that FSGS was associated with a higher risk of graft loss, perhaps because of selection of a UNOS data set filtered to match the SCOT IS protocol for making direct comparisons. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and steroid-free transplant patient data from the UNOS data for FSGS. SCOT recurrence rate for FSGS was 7.5%, which was lower than in most published single-center studies. Conclusions: Based on our results, we believe that it is safe to continue the steroid avoidance protocols at SCOT and the steroid-free protocol may not be detrimental when the adverse effects and toxicities associated with steroid use are considered.
Language	English
Publishing date	2021-08-05
Publishing country	United States
Document type	Journal Article
ISSN	2373-8731
ISSN	2373-8731
DOI	10.1097/TXD.0000000000001196
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Article ; Online: The Advantage of Multiple Listing Continues in the Kidney Allocation System Era.

Decoteau, Mary A / Stewart, Darren E / Toll, Alice E / Kurian, Sunil M / Case, Jamie / Marsh, Christopher L

Transplantation proceedings

2021 Volume 53, Issue 2, Page(s) 569–580

Abstract: Background: Transplant candidates can be listed at multiple transplant centers to increase the probability of receiving an organ. We evaluated the association between multilisting (ML) status and access to a deceased donor kidney transplant (DDKT) to ... ...

Abstract	Background: Transplant candidates can be listed at multiple transplant centers to increase the probability of receiving an organ. We evaluated the association between multilisting (ML) status and access to a deceased donor kidney transplant (DDKT) to determine if ML provides a long-term advantage regarding wait-list mortality and recipient outcomes. Materials and methods: Candidates between January 2010 and October 2017 were identified as either singly or multiply listed using Organ Procurement and Transplantation Network data and cohorts before and after implementation of the Kidney Allocation System (KAS). Cross-sectional logistic regression was used to assess relationships between candidate factors and ML prevalence (5.4%). Results: Factors associated with ML pre-KAS included having blood type B (reference, type O; odds ratio [OR], 1.20; P < .001), having private insurance (OR, 1.5; P < .001), wait time (OR, 1.28; P < .001), and increasing calculated panel-reactive antibody (cPRA) (reference, cPRA 0-100; OR for cPRA 80-98, 2.83; OR for cPRA 99, 3.47; OR for cPRA 100, 5.18; P < .001). Transplant rates were double for multilisted vs singly listed recipients (adjusted hazard ratio [aHR], 2.16; P < .001). Extra-donor service area ML candidates received transplants 2.5 years quicker than single-listing (SL) candidates, conferring a 42% wait-list advantage. Recipient death (aHR, 0.94; P = .122) and graft failure (aHR, 0.91; P = .006) rates were also lower for ML recipients. Conclusions: In the KAS era, ML continues to increase the likelihood of receiving a DDKT and lower the incidence of wait-list mortality, and it confers a survival advantages over SL.
MeSH term(s)	Adult ; Cross-Sectional Studies ; Female ; Health Plan Implementation ; Humans ; Incidence ; Kidney Transplantation/statistics & numerical data ; Logistic Models ; Male ; Middle Aged ; Odds Ratio ; Tissue Donors/supply & distribution ; Tissue and Organ Procurement/statistics & numerical data ; Waiting Lists/mortality
Language	English
Publishing date	2021-02-03
Publishing country	United States
Document type	Evaluation Study ; Journal Article
ZDB-ID	82046-5
ISSN	1873-2623 ; 0041-1345
ISSN (online)	1873-2623
ISSN	0041-1345
DOI	10.1016/j.transproceed.2020.10.036
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Article ; Online: Transcriptomic studies in tolerance: Lessons learned and the path forward.

Kurian, Sunil M / Whisenant, Thomas C / Mathew, James M / Miller, Joshua / Leventhal, Joseph R

Human immunology

2018 Volume 79, Issue 5, Page(s) 395–401

Abstract: Immunosuppression after solid organ transplantation is a delicate balance of the immune response and is a complex phenomenon with many factors involved. Despite advances in the care of patients receiving organ transplants the adverse effects associated ... ...

Abstract	Immunosuppression after solid organ transplantation is a delicate balance of the immune response and is a complex phenomenon with many factors involved. Despite advances in the care of patients receiving organ transplants the adverse effects associated with immunosuppressive agents and the risks of long-term immunosuppression present a series of challenges and the need to weigh the risks and benefits of either over or under-immunosuppression. Ideally, if all transplant recipients could develop donor-specific immunological tolerance, it could drastically improve long-term graft survival without the need for immunosuppressive agents. In the absence of this ideal situation, the next best approach would be to develop tools to determine the adequacy of immunosuppression in each patient, in a manner that would individualize or personalize therapy. Despite current genomics-based studies of tolerance biomarkers in transplantation there are currently, no clinically validated tools to safely increase or decrease the level of IS that is beneficial to the patient. However, the successful identification of biomarkers and/or mechanisms of tolerance that have implications on long-term graft survival and outcomes depend on proper integration of study design, experimental protocols, and data-driven hypotheses. The objective of this article is to first, discuss the progress made on genomic biomarkers of immunological tolerance and the future avenues for the development of such biomarkers specifically in kidney transplantation. Secondly, we provide a set of guiding principles and identify the pitfalls, advantages, and drawbacks of studies that generate genomic data aimed at understanding transplant tolerance that is applicable to all solid transplants.
MeSH term(s)	Animals ; Biomarkers/blood ; Biomarkers/metabolism ; Graft Rejection/genetics ; Graft Rejection/immunology ; Guidelines as Topic ; HLA Antigens/genetics ; HLA Antigens/immunology ; Humans ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/therapeutic use ; Kidney Transplantation/standards ; Kidney Transplantation/trends ; Liver Transplantation ; Transplantation Tolerance/drug effects ; Transplantation Tolerance/genetics ; Transplantation Tolerance/immunology
Chemical Substances	Biomarkers ; HLA Antigens ; Immunosuppressive Agents
Language	English
Publishing date	2018-03-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	801524-7
ISSN	1879-1166 ; 0198-8859
ISSN (online)	1879-1166
ISSN	0198-8859
DOI	10.1016/j.humimm.2018.02.011
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Article ; Online: Discovery and cross-validation of peripheral blood and renal biopsy gene expression signatures from ethnically diverse kidney transplant populations.

Ventura, Carlucci G / Whisenant, Thomas / Gelbart, Terri / David, Daisa S R / Agena, Fabiana / Salomon, Daniel R / David-Neto, Elias / Kurian, Sunil M

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

2019 Volume 19, Issue 12, Page(s) 3356–3366

Abstract: We determined peripheral blood (PB) and biopsy (Bx) RNA expression signatures in a Brazilian and US cohort of kidney transplant patients. Phenotypes assigned by precise histology were: acute rejection (AR), interstitial fibrosis/tubular atrophy/chronic ... ...

Abstract	We determined peripheral blood (PB) and biopsy (Bx) RNA expression signatures in a Brazilian and US cohort of kidney transplant patients. Phenotypes assigned by precise histology were: acute rejection (AR), interstitial fibrosis/tubular atrophy/chronic rejection (CR), excellent functioning transplants (TX), and glomerulonephritis recurrence (GN). Samples were analyzed on microarrays and profiles from each cohort were cross-validated on the other cohort with similar phenotypes. We discovered signatures for each tissue: (1) AR vs TX, (2) CR vs TX, and (3) GN vs TX using the Random Forests algorithm. We validated biopsies signatures of AR vs TX (area under the curve [AUC] 0.97) and CR vs TX (AUC 0.87). We also validated both PB and Bx signatures of AR vs TX and CR vs TX with varying degrees of accuracy. Several biological pathways were shared between AR and CR, suggesting similar rejection mechanisms in these 2 clinical phenotypes. Thus, we identified gene expression signatures for AR and CR in transplant patients and validated them in independent cohorts of significantly different racial/ethnic backgrounds. These results reveal that there are strong unifying immune mechanisms driving transplant diseases and identified in the signatures discovered in each cohort, suggesting that molecular diagnostics across populations are feasible despite ethnic and environmental differences.
MeSH term(s)	Adolescent ; Adult ; Aged ; Biomarkers/analysis ; Biopsy ; Cohort Studies ; Ethnicity/genetics ; Female ; Follow-Up Studies ; Gene Expression Profiling ; Graft Rejection/blood ; Graft Rejection/diagnosis ; Graft Rejection/etiology ; Graft Survival ; Humans ; Kidney Failure, Chronic/surgery ; Kidney Transplantation/adverse effects ; Leukocytes, Mononuclear/metabolism ; Male ; Middle Aged ; Prognosis ; Transcriptome ; Young Adult
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2060594-8
ISSN	1600-6143 ; 1600-6135
ISSN (online)	1600-6143
ISSN	1600-6135
DOI	10.1111/ajt.15482
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