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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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Zs.A 5609: Show issues

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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: 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: Digital imaging software versus the "eyeball" method in quantifying steatosis in a liver biopsy.

Long, Jane J / Nijhar, Kieranjeet / Jenkins, Reed T / Yassine, Adham / Motter, Jennifer D / Jackson, Kyle R / Jerman, Stephanie / Besharati, Sepideh / Anders, Robert A / Dunn, Ty B / Marsh, Christopher L / Rayapati, Divya / Lee, David D / Barth, Rolf N / Woodside, Kenneth J / Philosophe, Benjamin

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society

2023 Volume 29, Issue 3, Page(s) 268–278

Abstract: Steatotic livers represent a potentially underutilized resource to increase the donor graft pool; however, 1 barrier to the increased utilization of such grafts is the heterogeneity in the definition and the measurement of macrovesicular steatosis (MaS). ...

Abstract	Steatotic livers represent a potentially underutilized resource to increase the donor graft pool; however, 1 barrier to the increased utilization of such grafts is the heterogeneity in the definition and the measurement of macrovesicular steatosis (MaS). Digital imaging software (DIS) may better standardize definitions to study posttransplant outcomes. Using HALO, a DIS, we analyzed 63 liver biopsies, from 3 transplant centers, transplanted between 2016 and 2018, and compared macrovesicular steatosis percentage (%MaS) as estimated by transplant center, donor hospital, and DIS. We also quantified the relationship between DIS characteristics and posttransplant outcomes using log-linear regression for peak aspartate aminotransferase, peak alanine aminotransferase, and total bilirubin on postoperative day 7, as well as logistic regression for early allograft dysfunction. Transplant centers and donor hospitals overestimated %MaS compared with DIS, with better agreement at lower %MaS and less agreement for higher %MaS. No DIS analyzed liver biopsies were calculated to be >20% %MaS; however, 40% of liver biopsies read by transplant center pathologists were read to be >30%. Percent MaS read by HALO was positively associated with peak aspartate aminotransferase (regression coefficient= 1.04 1.08 1.12 , p <0.001), peak alanine aminotransferase (regression coefficient = 1.04 1.08 1.12 , p <0.001), and early allograft dysfunction (OR= 1.10 1.40 1.78 , p =0.006). There was no association between HALO %MaS and total bilirubin on postoperative day 7 (regression coefficient = 0.99 1.01 1.04 , p =0.3). DIS provides reproducible quantification of steatosis that could standardize MaS definitions and identify phenotypes associated with good clinical outcomes to increase the utilization of steatite livers.
MeSH term(s)	Humans ; Alanine Transaminase ; Aspartate Aminotransferases ; Bilirubin ; Biopsy ; Fatty Liver/diagnostic imaging ; Fatty Liver/pathology ; Liver/diagnostic imaging ; Liver/pathology ; Liver Transplantation/methods ; Software ; Image Processing, Computer-Assisted/methods
Chemical Substances	Alanine Transaminase (EC 2.6.1.2) ; Aspartate Aminotransferases (EC 2.6.1.1) ; Bilirubin (RFM9X3LJ49)
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2006866-9
ISSN	1527-6473 ; 1527-6465
ISSN (online)	1527-6473
ISSN	1527-6465
DOI	10.1097/LVT.0000000000000064
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Zs.A 4702: Show issues

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Article ; Online: Feasibility and Comparison Study of Fecal Sample Collection Methods in Healthy Volunteers and Solid Organ Transplant Recipients Using 16S rRNA and Metagenomics Approaches.

Kurian, Sunil M / Gordon, Skyler / Barrick, Bethany / Dadlani, Manoj N / Fanelli, Brian / Cornell, Jenny B / Head, Steven R / Marsh, Christopher L / Case, Jamie

Biopreservation and biobanking

2020 Volume 18, Issue 5, Page(s) 425–440

Abstract: The human microbiome encompasses a variety of microorganisms that change dynamically and are in close contact with the body. The microbiome influences health and homeostasis, as well as the immune system, and any significant change in this equilibrium ( ... ...

Abstract	The human microbiome encompasses a variety of microorganisms that change dynamically and are in close contact with the body. The microbiome influences health and homeostasis, as well as the immune system, and any significant change in this equilibrium (dysbiosis) triggers both acute and chronic health conditions. Microbiome research has surged, in part, due to advanced sequencing technologies enabling rapid, accurate, and cost-effective identification of the microbiome. A major prerequisite for stool sample collection to study the gut microbiome in longitudinal prospective studies requires standardized protocols that can be easily replicated. However, there are still significant bottlenecks to stool specimen collection that contribute to low patient retention rates in microbiome studies. These barriers are further exacerbated in solid organ transplant recipients where diarrhea is estimated to occur in up to half the patient population. We sought to test two relatively easy sample collection methods (fecal swab and wipes) and compare them to the more cumbersome "gold" standard collection method (scoop) using two different sequencing technologies (16S ribosomal RNA sequencing and shotgun metagenomics). Our comparison of the collection methods shows that both the swabs and the wipes are comparable to the scoop method in terms of bacterial abundance and diversity. The swabs, however, were closer in representation to the scoop and were easier to collect and process compared to the wipes. Potential contamination of the swab and the wipe samples by abundant skin commensals was low in our analysis. Comparison of the two sequencing technologies showed that they were complementary, and that 16S sequencing provided enough coverage to detect and differentiate between bacterial species identified in the collected samples. Our pilot study demonstrates that alternative collection methods for stool sampling are a viable option in clinical applications, such as organ transplant studies. The use of these methods may result in better patient retention recruitment rates in serial microbiome studies.
MeSH term(s)	Feasibility Studies ; Feces ; Healthy Volunteers ; Humans ; Metagenomics ; Organ Transplantation ; Pilot Projects ; Prospective Studies ; RNA, Ribosomal, 16S
Chemical Substances	RNA, Ribosomal, 16S
Language	English
Publishing date	2020-08-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2593993-2
ISSN	1947-5543 ; 1947-5535
ISSN (online)	1947-5543
ISSN	1947-5535
DOI	10.1089/bio.2020.0032
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Article ; Online: Safety and Efficacy of a Steroid Avoidance Immunosuppression Regimen in Renal Transplant Patients With De Novo or Preformed Donor-Specific Antibodies: A Single-Center Study.

Schutt, Ryan / Case, Jamie / Kurian, Sunil M / Spierling Bagsic, Samantha R / Barrick, Bethany L / Toll, Alice E / Zhang, Qiuheng / Reed, Elaine F / Quigley, Michael M / Schaffer, Randolph / Fisher, Jonathan S / Rice, James C / Marsh, Christopher L

Transplantation proceedings

2020 Volume 53, Issue 3, Page(s) 950–961

Abstract: Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly ... ...

Abstract	Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection.
MeSH term(s)	Adult ; Cohort Studies ; Female ; Graft Rejection/immunology ; Graft Survival/immunology ; HLA Antigens/immunology ; Humans ; Immunosuppression/methods ; Isoantibodies/immunology ; Kidney Transplantation/methods ; Male ; Middle Aged ; Steroids ; Transplant Recipients
Chemical Substances	HLA Antigens ; Isoantibodies ; Steroids
Language	English
Publishing date	2020-12-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	82046-5
ISSN	1873-2623 ; 0041-1345
ISSN (online)	1873-2623
ISSN	0041-1345
DOI	10.1016/j.transproceed.2020.10.021
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Article ; Online: Combining Blood Gene Expression and Cellfree DNA to Diagnose Subclinical Rejection in Kidney Transplant Recipients.

Park, Sookhyeon / Guo, Kexin / Heilman, Raymond L / Poggio, Emilio D / Taber, David J / Marsh, Christopher L / Kurian, Sunil M / Kleiboeker, Steve / Weems, Juston / Holman, John / Zhao, Lihui / Sinha, Rohita / Brietigam, Susan / Rebello, Christabel / Abecassis, Michael M / Friedewald, John J

Clinical journal of the American Society of Nephrology : CJASN

2021 Volume 16, Issue 10, Page(s) 1539–1551

Abstract: Background and objectives: Subclinical acute rejection is associated with poor outcomes in kidney transplant recipients. As an alternative to surveillance biopsies, noninvasive screening has been established with a blood gene expression profile. Donor- ... ...

Abstract	Background and objectives: Subclinical acute rejection is associated with poor outcomes in kidney transplant recipients. As an alternative to surveillance biopsies, noninvasive screening has been established with a blood gene expression profile. Donor-derived cellfree DNA (cfDNA) has been used to detect rejection in patients with allograft dysfunction but not tested extensively in stable patients. We hypothesized that we could complement noninvasive diagnostic performance for subclinical rejection by combining a donor-derived cfDNA and a gene expression profile assay. Design, setting, participants, & measurements: We performed a Results: For diagnosing subclinical rejection, the gene expression profile demonstrated a negative predictive value of 82%, a positive predictive value of 47%, a balanced accuracy of 64%, and an area under the receiver operating curve of 0.75. The donor-derived cfDNA assay showed similar negative predictive value (84%), positive predictive value (56%), balanced accuracy (68%), and area under the receiver operating curve (0.72). When both assays were negative, negative predictive value increased to 88%. When both assays were positive, positive predictive value increased to 81%. Combining assays using multivariable logistic regression, area under the receiver operating curve was 0.81, significantly higher than the gene expression profile ( Conclusions: A combination of blood-based biomarkers can improve detection and provide less invasive monitoring for subclinical rejection. In this study, the gene expression profile detected more cellular rejection, whereas donor-derived cfDNA detected more antibody-mediated rejection.
MeSH term(s)	Adult ; Asymptomatic Diseases ; Biomarkers/blood ; Biopsy ; Cell-Free Nucleic Acids/blood ; Cell-Free Nucleic Acids/genetics ; DNA/blood ; DNA/genetics ; Female ; Gene Expression Profiling ; Graft Rejection/blood ; Graft Rejection/diagnosis ; Graft Rejection/genetics ; Graft Rejection/immunology ; Humans ; Kidney Transplantation/adverse effects ; Male ; Middle Aged ; Predictive Value of Tests ; Reproducibility of Results ; Tissue Donors ; Transcriptome ; Treatment Outcome ; United States ; Young Adult
Chemical Substances	Biomarkers ; Cell-Free Nucleic Acids ; DNA (9007-49-2)
Language	English
Publishing date	2021-10-07
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Multicenter Study ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2226665-3
ISSN	1555-905X ; 1555-9041
ISSN (online)	1555-905X
ISSN	1555-9041
DOI	10.2215/CJN.05530421
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