Publications by authors named "Ian W Gibson"

62 Publications

Two Cases of Sporadic Eosinophilic Solid and Cystic Renal Cell Carcinoma in Manitoba Population.

Int J Surg Pathol 2021 Feb 22:1066896921993229. Epub 2021 Feb 22.

Department of Pathology, 8664University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada.

Two sporadic cases of eosinophilic solid and cystic renal cell carcinoma (ESC RCC), at our institution, are presented in this study to contribute to the growing literature on this novel renal neoplasm. The first patient was a 38-year-old female with two synchronous renal masses measuring 3.5 and 1.9 cm on preoperative imaging. The second patient was a 44-year-old female with an incidental renal mass measuring 4 cm. Both patients underwent uncomplicated radical nephrectomies. The 1.9 cm mass in the first patient was consistent with clear cell RCC. The dominant mass in the first patient and the tumor in the second patient had microscopic and macroscopic findings in keeping with ESC RCC including a tan appearance, abundant eosinophilic cytoplasm, and CK20+ and CK7- staining. Both patients had an uncomplicated course following surgery with no evidence of local recurrence or distant metastatic disease for 1 and 2 years for the first and second patient accordingly. These cases contribute to a growing body of literature regarding ESC RCC including, to our knowledge, the first reported case of synchronous ESC RCC and clear cell RCC. Further research about this novel renal neoplasm is needed.
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http://dx.doi.org/10.1177/1066896921993229DOI Listing
February 2021

Age and sex determine conversion from immediate-release to extended-release tacrolimus in a multi-center cohort of Canadian pediatric renal transplant recipients.

Pediatr Transplant 2020 Dec 23:e13959. Epub 2020 Dec 23.

Pediatric Nephrology, The University of British Columbia, Vancouver, BC, Canada.

ER-Tac, taken once per day, is associated with improved adherence. This study examined the potential patient and clinical factors that influence clinicians to convert pediatric patients from immediate-release to ER-Tac. This prospective multi-center observational study followed Canadian pediatric kidney transplant recipients up to 5 years post-transplant. Cox Proportional Hazards Regression was used to examine the influence of factors on conversion to ER-Tac. Sixty-six participants were included in this analysis. For every additional year of age at the time of transplant, the likelihood of conversion was more than doubled (HR 2.54, CI 1.83, 3.54, P < 0.001). The impact of age reduced by three percent for every month after transplant (HR 0.97, CI 0.95, 0.98, P < 0.001). Girls were more likely to be converted than boys (HR 3.78, CI 1.35, 10.6, P 0.01). Adherence measures (MAM-MM and tacrolimus trough variability), individual barriers to adherence, renal function, HLA mismatch, and rejection were not significant predictors of conversion in the final regression model. ER-Tac was preferentially prescribed to older age and female patients. Female sex and adolescence are both associated with worse graft outcomes, but we found no link between individualized markers of adherence/graft risk and conversion. Clinicians appeared to be using demographic features to distinguish patients at perceived higher risk and converted accordingly, without a case-by-case evaluation of who is more susceptible to poor outcomes.
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http://dx.doi.org/10.1111/petr.13959DOI Listing
December 2020

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients.

Am J Transplant 2020 Oct 8. Epub 2020 Oct 8.

Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada.

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66-0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66-0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = -0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.
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http://dx.doi.org/10.1111/ajt.16336DOI Listing
October 2020

Early surveillance biopsy utilization and management of pediatric renal allograft acute T cell-mediated rejection in Canadian centers: Observations from the PROBE multicenter cohort study.

Pediatr Transplant 2021 Mar 7;25(2):e13870. Epub 2020 Oct 7.

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Background: Early TCMR surveillance with protocol kidney biopsy is used differentially among pediatric kidney transplant centers. Little has been reported about actual center-based differences, and this variability may influence TCMR ascertainment, treatment, and monitoring more broadly.

Methods: Data from the PROBE multicenter study were used to identify patients from centers conducting ESB or LSIB. ESB was defined as >50% of patients having at least 1 surveillance biopsy in the first 9 months. Patients were compared for number of biopsies, rejection episodes, treatment, and follow-up monitoring.

Results: A total of 261 biopsies were performed on 97 patients over 1-2 years of follow-up. A total of 228 (87%) of biopsies were performed in ESB centers. Compared to LSIB centers, ESB centers had 7-fold more episodes of TCMR diagnosed on any biopsy [0.8 ± 1.2 vs 0.1 ± 0.4; P < .001] and a 3-fold higher rate from indication biopsies [0.3 ± 0.9 vs 0.1 ± 0.3; P = .04]. The proportion of rejection treatment varied based on severity: Banff borderline i1t1 (40%);>i1t1 and < Banff 1A (86%); and ≥ Banff 1A (100%). Biopsies for follow-up were performed after treatment in 80% of cases (n = 28) of rejection almost exclusively at ESB centers, with 17 (61%) showing persistence of TCMR (≥i1t1).

Conclusions: Practice variation exists across Canadian pediatric renal transplant centers with ESB centers identifying more episodes of rejection. Additionally, treatment of Banff borderline is not universal and varies with severity regardless of center type. Lastly, follow-up biopsies are performed inconsistently and invariably show persistence of rejection.
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http://dx.doi.org/10.1111/petr.13870DOI Listing
March 2021

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation.

Am J Transplant 2020 Sep 21. Epub 2020 Sep 21.

Translational Transplant Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.
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http://dx.doi.org/10.1111/ajt.16311DOI Listing
September 2020

Langerhans Cell Histiocytosis Associated With Renal Cell Carcinoma Is a Neoplastic Process: Clinicopathologic and Molecular Study of 7 Cases.

Am J Surg Pathol 2020 12;44(12):1658-1665

Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder composed of Langerhans cells admixed with reactive mononuclear and granulocytic cells, associated with prominent eosinophils. LCH is considered a neoplasm, driven in most cases by oncogenic RAS/RAF/MEK/ERK pathway mutations. The disease predominantly affects children. Urinary system involvement has rarely been reported in a multisystem disease setting. We describe 7 patients who presented with LCH occurring within (6 cases) or after (1 case) a resected clear cell (n=6) or clear cell papillary (n=1) renal cell carcinoma (RCC), identified prospectively in our routine and consultation files (2012 to 2019). The patients included 5 women and 2 men, with a median age of 54 years (range, 39 to 73 y), none with a history of LCH or LCH manifestations before the time of RCC diagnosis. The median size of the RCC was 3.5 cm (range, 1.8 to 8.3 cm). Treatment included partial (5 cases), or radical (2 cases) nephrectomy. All RCCs on gross examination showed at least focal cystic changes and were low grade (World Health Organization [WHO]/International Society of Urologic Pathologists [ISUP] grade 1 to 2). The LCH foci were detected as incidental histological finding within the resected RCC in all six cases and they were limited to few high-power fields (<2 mm) in 5 of 6 cases, but in the sixth case, they occupied almost the entire clear cell papillary RCC (2 cm nodule). No LCH manifestations were detected in the normal kidney or in perinephric fat. The seventh patient developed LCH within inguinal deep soft tissue followed by systemic manifestations 6 years after clear cell RCC. Langerhans cell immunophenotype was supported by the reactivity for S-100, CD1a, and langerin and by the negative pankeratin. Successful pyrosequencing of microdissected LCH DNA revealed the V600E BRAF mutation in all 6 cases of LCH within RCC. To our knowledge, only 3 similar cases were published since 1980; the only case tested for BRAF mutation showed wild-type BRAF. This is the first study analyzing the morphologic and genetic features of a cohort of LCH associated with RCC. In our experience, these cases may be underrecognized in practice, or may erroneously be diagnosed as RCC dedifferentiation or high-grade sarcomatoid transformation. Finally, the detection of BRAF mutation further confirms that LCH in this setting is indeed a neoplasm, rather than a reactive lesion.
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http://dx.doi.org/10.1097/PAS.0000000000001562DOI Listing
December 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Am J Transplant 2020 09 9;20(9):2499-2508. Epub 2020 Apr 9.

Department of Medicine, University of Manitoba, Winnipeg, Canada.

Prognostic biomarkers of T cell-mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA-DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor-specific antibodies (P = .002). HLA-DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA-DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA-DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA-DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA-DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.
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http://dx.doi.org/10.1111/ajt.15860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496654PMC
September 2020

Hyperacute Antibody-mediated Rejection Associated With Red Blood Cell Antibodies.

Transplant Direct 2019 Aug 25;5(8):e477. Epub 2019 Jul 25.

Section of Nephrology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

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http://dx.doi.org/10.1097/TXD.0000000000000925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708630PMC
August 2019

Early Antibody-Mediated Kidney Transplant Rejection Associated With Anti-Vimentin Antibodies: A Case Report.

Am J Kidney Dis 2020 01 9;75(1):138-143. Epub 2019 Sep 9.

Section of Nephrology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address:

Improving precision in predicting alloreactivity is an important unmet need and may require individualized consideration of non-HLA antibodies. We report a 21-year-old man with kidney failure from immunoglobulin A nephropathy who met all traditional criteria for a "low-risk" transplant for immune memory. He was unsensitized and received a haplotype-matched living donor kidney transplant from his mother. There were no anti-HLA donor-specific antibodies and flow cross-match was negative. After immediate function, he developed delayed graft function on postoperative day 2. The transplant biopsy specimen was suggestive of antibody-mediated rejection and acute tubular injury with increased vimentin proximal tubular expression compared to the implantation biopsy specimen. He had a history of juvenile idiopathic arthritis, and non-HLA antibody screening demonstrated preformed anti-vimentin antibody. He was successfully treated with plasmapheresis, intravenous immunoglobulin, antithymocyte globulin, and methylprednisolone, with renal recovery. The follow-up biopsy specimen demonstrated decreased vimentin expression with decreased alloinflammation, and graft function remains stable at 1 year posttransplantation (estimated glomerular filtration rate, 62mL/min/1.73m). We postulate that preformed anti-vimentin autoantibodies bound to vimentin expressed on apoptotic tubular epithelial cells induced by ischemia-reperfusion injury and to constitutively expressed vimentin on peritubular capillaries and podocytes. Our case is suggestive of the involvement of anti-vimentin antibody, for which the pathogenic epitopes may be exposed during ischemia-reperfusion injury.
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http://dx.doi.org/10.1053/j.ajkd.2019.06.010DOI Listing
January 2020

Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients.

BMJ Open 2019 04 11;9(4):e024908. Epub 2019 Apr 11.

Internal Medicine, University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada.

Introduction: Subclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients.

Methods And Analysis: This is a phase ii/iii multicentre, international randomised controlled parallel group trial to determine if the early treatment of rejection, as detected by urine CXCL10, will improve kidney allograft outcomes. Incident adult kidney transplant patients (n~420) will be enrolled to undergo routine urine CXCL10 monitoring postkidney transplant. Patients at high risk of rejection, defined as confirmed elevated urine CXCL10 level, will be randomised 1:1 stratified by centre (n=250). The intervention arm (n=125) will undergo a study biopsy to check for subclinical rejection and biopsy-proven rejection will be treated per protocol. The control arm (n=125) will undergo routine post-transplant monitoring. The primary outcome at 12 months is a composite of death-censored graft loss, clinical biopsy-proven acute rejection, de novo donor-specific antibody, inflammation in areas of interstitial fibrosis and tubular atrophy (Banff i-IFTA, chronic active T-cell mediated rejection) and subclinical tubulitis on 12-month surveillance biopsy. The secondary outcomes include decline of graft function, microvascular inflammation at 12 months, development of IFTA at 12 months, days from transplantation to clinical biopsy-proven rejection, albuminuria, EuroQol five-dimension five-level instrument, cost-effectiveness analysis of the urine CXCL10 monitoring strategy and the urine CXCL10 kinetics in response to rejection therapy.

Ethics And Dissemination: The study has been approved by the University of Manitoba Health Research Ethics Board (HS20861, B2017:076) and the local research ethics boards of participating centres. Recruitment commenced in March 2018 and results are expected to be published in 2023. De-identified data may be shared with other researchers according to international guidelines (International Committee of Medical Journal Editors [ICJME]).

Trial Registration Number: NCT03206801; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-024908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500325PMC
April 2019

Subclinical Inflammation in Renal Transplantation.

Transplantation 2019 06;103(6):e139-e145

Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

The standardization of renal allograft pathology began in 1991 at the first Banff Conference held in Banff, Alberta, Canada. The first task of transplant pathologists, clinicians, and surgeons was to establish diagnostic criteria for T-cell-mediated rejection (TCMR). The histological threshold for this diagnosis was arbitrarily set at "i2t2": a mononuclear interstitial cell infiltrate present in at least 25% of normal parenchyma and >4 mononuclear cells within the tubular basement membrane of nonatrophic tubules. TCMR was usually found in dysfunctional grafts with an elevation in the serum creatinine; however, our group and others found this extent of inflammation in "routine" or "protocol" biopsies of normally functioning grafts: "subclinical" TCMR. The prevalence of TCMR is higher in the early months posttransplant and has decreased with the increased potency of current immunosuppressive agents. However, the pathogenicity of lesser degrees of inflammation under modern immunosuppression and the relation between ongoing inflammation and development of donor-specific antibody has renewed our interest in subclinical alloreactivity. Finally, the advances in our understanding of pretransplant risk assessment, and our increasing ability to monitor patients less invasively posttransplant, promises to usher in the era of precision medicine.
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http://dx.doi.org/10.1097/TP.0000000000002682DOI Listing
June 2019

Non-invasive differentiation of non-rejection kidney injury from acute rejection in pediatric renal transplant recipients.

Pediatr Transplant 2019 05 4;23(3):e13364. Epub 2019 Feb 4.

Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

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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http://dx.doi.org/10.1111/petr.13364DOI Listing
May 2019

HLA-DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity.

Am J Transplant 2019 06 15;19(6):1708-1719. Epub 2018 Dec 15.

Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA-DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA-DR/DQ whole antigen mismatch, HLA-DR/DQ single molecule eplet mismatch improved the correlation with de novo donor-specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell-mediated rejection (P = .0006), HLA-DR/DQ de novo donor-specific antibody development (P < .0001), antibody-mediated rejection (P < .0001), as well as all-cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA-DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.
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http://dx.doi.org/10.1111/ajt.15177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563434PMC
June 2019

Quality and Quantity in Kidney Cancer Surgery: The Role of Nonneoplastic Kidney and Kidney Volumetrics in Predicting Postoperative Renal Function.

Am J Clin Pathol 2019 01;151(1):108-115

Department of Urology, Queens University, Kingston, Canada.

Objectives: To model renal function 2 years following radical nephrectomy with quantitative analyses using clinical, histopathologic, and renal composite cortical volumes (CCV).

Methods: This retrospective study involved an assessment of the nonneoplastic kidney tissue by three blinded nephropathologists using modified Banff 1997 criteria for renal allograft pathology. Volumetric image acquisition was obtained by three independent radiologists using preoperative imaging. A 2-year estimated glomerular filtration (eGFR) calculator was created.

Results: Among the 126 patients, median age was 60 years; median CCV, 398.1 cm3; preoperative eGFR, 77 mL/min/1.73 m2; and 2-year postoperative eGFR, 54 mL/min/1.73 m2. Of the subjects, 64% had hypertension, 26% diabetes, and 37% were smokers. Increasing age, glomerulopathy/sclerosis, tubulointerstitial scarring, and arteriosclerosis were statistically significantly and adversely associated with eGFR. Conversely, increasing CCV was associated with a higher eGFR.

Conclusions: Quantitative analysis of the nephrectomized kidney in conjunction with patient age can accurately predict renal function at 2 years.
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http://dx.doi.org/10.1093/ajcp/aqy107DOI Listing
January 2019

Non-invasive staging of chronic kidney allograft damage using urine metabolomic profiling.

Pediatr Transplant 2018 08 31;22(5):e13226. Epub 2018 May 31.

Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.

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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http://dx.doi.org/10.1111/petr.13226DOI Listing
August 2018

Disseminated Mycobacterium bovis infection post-kidney transplant following remote intravesical BCG therapy for bladder cancer.

Transpl Infect Dis 2018 Oct 13;20(5):e12931. Epub 2018 Jun 13.

Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Intravesical Bacillus Camlette-Guérin (BCG) is the treatment of choice for non-muscle invasive bladder cancer, and has been used successfully for over 40 years. A rare and potentially fatal complication of intravesical BCG therapy is BCG-induced sepsis. We report a rare case in which a patient with end-stage renal disease secondary to chronic granulomatous interstitial nephritis underwent remote, pre-transplant intravesical BCG treatment for high-grade non-invasive papillary bladder carcinoma. The patient subsequently received a deceased donor kidney transplant 5 years after BCG therapy, with thymoglobulin induction therapy and standard triple maintenance immunosuppression. Two years post-transplant, he developed BCG-induced sepsis confirmed by cultures from urine, blood, and left native kidney biopsy. He died from disseminated BCG-induced sepsis and failure of his renal allograft. This case highlights the potential adverse reactions associated with intravesical BCG therapy that may occur years after bladder cancer therapy is completed, and should heighten physician awareness for BCG-related infections during pre-transplant assessment and post-transplant care of solid organ transplants recipients.
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http://dx.doi.org/10.1111/tid.12931DOI Listing
October 2018

The prognostic value of urinary chemokines at 6 months after pediatric kidney transplantation.

Pediatr Transplant 2018 08 7;22(5):e13205. Epub 2018 May 7.

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Pediatric kidney transplantation is lifesaving, but long-term allograft survival is still limited by injury processes mediated by alloimmune inflammation that may otherwise be clinically silent. Chemokines associated with alloimmune inflammation may offer prognostic value early post-transplant by identifying patients at increased risk of poor graft outcomes. We conducted a single-center prospective cohort study of consecutive pediatric kidney transplant recipients (<19 years). Urinary CCL2 and CXCL10 measured at 6 months post-transplant were evaluated for association with long-term eGFR decline, allograft survival, and concomitant acute cellular rejection histology. Thirty-eight patients with a mean age of 12.4 ± 4.6 years were evaluated. Urinary CCL2 was associated with eGFR decline until 6 months (ρ -0.43; P < .01), but not at later time points. Urinary CXCL10 was associated with eGFR decline at 36 months (ρ -0.49; P < .01), risk of 50% eGFR decline (HR = 1.04; P = .02), risk of allograft loss (HR = 1.05; P = .01), borderline rejection or rejection episodes 6-12 months post-transplant (r .41; P = .02), and Banff i + t score (r .47, P < .01). CCL2 and CXCL10 were also correlated with one another (ρ 0.54; P < .01). CCL2 and CXCL10 provide differing, but complementary, information that may be useful for early non-invasive prognostic testing in pediatric kidney transplant recipients.
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http://dx.doi.org/10.1111/petr.13205DOI Listing
August 2018

Evolution of renal function and urinary biomarker indicators of inflammation on serial kidney biopsies in pediatric kidney transplant recipients with and without rejection.

Pediatr Transplant 2018 08 25;22(5):e13202. Epub 2018 Apr 25.

Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.

Urinary CXCL10 and metabolites are biomarkers independently associated with TCMR. We sought to test whether these biomarkers fluctuate in association with histological severity of TCMR over short time frames. Forty-nine pairs of renal biopsies obtained 1-3 months apart from 40 pediatric renal transplant recipients were each scored for TCMR acuity score (i + t; Banff criteria). Urinary CXCL10:Cr and TCMR MDS were obtained at each biopsy and were tested for association with changes between biopsies in acuity, estimated GFR (ΔeGFR), and 12-month ΔeGFR. Sequential biopsies were obtained 1.8 ± 0.8 months apart. Biopsy 1 was usually obtained under protocol (75%), and 62% percent had evidence of TCMR. Using each biopsy pair for comparison, ΔeGFR did not predict change in acuity. By contrast, change in acuity was significantly correlated with change in urinary CXCL10:Cr (ρ 0.45, P = .003) and MDS (ρ 0.29, P = .04) between biopsies. The 12-month ΔeGFR was not predicted by TCMR acuity or CXCL10:Cr at Biopsy 2; however, an inverse correlation was seen with urinary MDS (ρ -0.35; P = .02). Changes in eGFR correlate poorly with evolving TCMR acuity on histology. Urinary biomarkers may be superior for non-invasive monitoring of rejection, including histological response to therapy, and may be prognostic for medium-term function.
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http://dx.doi.org/10.1111/petr.13202DOI Listing
August 2018

Carpe diem-Time to transition from empiric to precision medicine in kidney transplantation.

Am J Transplant 2018 07 30;18(7):1615-1625. Epub 2018 Apr 30.

Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.

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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http://dx.doi.org/10.1111/ajt.14746DOI Listing
July 2018

Pre-transplant ATR antibodies correlate with early allograft rejection.

Transpl Immunol 2018 02 5;46:29-35. Epub 2017 Dec 5.

Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.

Studies investigating the potential pathogenic effects of non-HLA antibodies (Ab) have identified Ab against the angiotensin II type 1 receptor (ATR-Ab) as a risk factor for rejection and kidney graft loss. This study sought to validate the risk of ATR-Ab for acute rejection and to explore the role of other non-HLA Abs in this capacity. Pre- and post-transplant sera from a cohort of 101 patients (n=453 samples total) were tested for ATR-Ab and other non-HLA Ab using a commercially available ELISA kit and the Luminex platform, respectively. Patients positive for pre-transplant ATR-Ab were more likely to develop de novo donor-specific Ab (dnDSA) compared to patients that were negative for ATR-Ab (28% vs 10%, p=0.027). Pre-transplant positivity for ATR-Ab was associated with TCMR in the first year post-transplant (p=0.034), but did not predict graft loss independent of dnDSA (p=0.063). ATR-Ab positivity was significantly associated with positivity for Ab against the endothelin A type 1 receptor (ETR-Ab) inclusive of all study time points (p=0.0021). Given the high prevalence of ATR-Ab pre-transplant (20%) and its association with dnDSA and early TCMR, a prospective study to determine if more intense immunosuppression and/or ATR blockade has an impact on outcomes in these patients is warranted.
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http://dx.doi.org/10.1016/j.trim.2017.12.001DOI Listing
February 2018

Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study.

Am J Physiol Renal Physiol 2018 03 15;314(3):F412-F422. Epub 2017 Nov 15.

Department of Medicine, Division of Nephrology, University Health Network, University of Toronto , Toronto, Ontario , Canada.

Focal segmental glomerulosclerosis (FSGS) is an important cause of nondiabetic chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibition (SGLT2i) therapy attenuates the progression of diabetic nephropathy, but it remains unclear whether SGLT2i provides renoprotection in nondiabetic CKD such as FSGS. The primary aim of this pilot study was to determine the effect of 8 wk of dapagliflozin on glomerular filtration rate (GFR) in humans and in experimental FSGS. Secondary end points were related to changes in renal hemodynamic function, proteinuria, and blood pressure (BP). GFR (inulin) and renal plasma flow (para-aminohippurate), proteinuria, and BP were measured in patients with FSGS ( n = 10), and similar parameters were measured in subtotally nephrectomized (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow, and 24-h urine protein excretion were not statistically significant in humans or rats. Systolic BP (SBP) decreased in SNx rats (196 ± 26 vs. 165 ± 33 mmHg; P < 0.001), whereas changes were not statistically significant in humans (SBP 112.7 ± 8.5 to 112.8 ± 11.2 mmHg, diastolic BP 71.8 ± 6.5 to 69.6 ± 8.4 mmHg; P = not significant), although hematocrit increased (0.40 ± 0.05 to 0.42 ± 0.05%; P = 0.03). In archival kidney tissue from a separate patient cohort, renal parenchymal SGLT2 mRNA expression was decreased in individuals with FSGS compared with controls. Short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS. This may be related to downregulation of renal SGLT2 expression. Studies examining the impact of SGLT2i on markers of kidney disease in patients with other causes of nondiabetic CKD are needed.
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http://dx.doi.org/10.1152/ajprenal.00445.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899226PMC
March 2018

Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development.

J Am Soc Nephrol 2017 Nov 20;28(11):3353-3362. Epub 2017 Jul 20.

Departments of Medicine.

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II donor-specific antibody (DSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before DSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of DSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of DSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ DSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before DSA development were significantly lower than the levels >6 months before DSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing DSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of DSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for DSA may be advisable in this setting.
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http://dx.doi.org/10.1681/ASN.2017030287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661295PMC
November 2017

ANCA Associated Vasculitis Secondary to Levamisole-Adultered Cocaine with Associated Membranous Nephropathy: A Case Series.

Am J Nephrol 2017 28;45(3):209-216. Epub 2017 Jan 28.

Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.

Background: Cocaine is a risk factor for acute kidney injury and chronic kidney disease with progression to end-stage renal disease. Levamisole is an adulterant that is added to cocaine to enhance its euphoric effects. Levamisole-adulterated cocaine (LAC) is associated with the distinct clinical syndromes of agranulocytosis, leukocytoclastic vasculitis, cocaine-induced midline destructive lesions (CIMDL), and ANCA-associated vasculitis (AAV) with pauci-immune necrotizing glomerulonephritis.

Methods: We reviewed all cases of AAV secondary to LAC at our institution.

Results: We report 3 cases of AAV secondary to LAC and associated membranous nephropathy (MN). The first and second cases are concurrent AAV secondary to LAC and associated MN while the third case involves the development of MN after AAV secondary to LAC.

Conclusions: Clinicians should be aware of this novel association of LAC with MN.
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http://dx.doi.org/10.1159/000456553DOI Listing
December 2017

Urinary Metabolomics for Noninvasive Detection of Antibody-Mediated Rejection in Children After Kidney Transplantation.

Transplantation 2017 10;101(10):2553-2561

1 Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, BC, Canada. 2 Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada. 3 Department of Pathology, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 4 The Metabolomics Innovation Center, University of Alberta, Edmonton, AB, Canada. 5 Section of Nephrology, Department of Internal Medicine, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 6 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. 7 Manitoba Center for Proteomics and Systems Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: Biomarkers are needed that identify patients with antibody-mediated rejection (AMR). The goal of this study was to evaluate the utility of urinary metabolomics for early noninvasive detection of AMR in pediatric kidney transplant recipients.

Methods: Urine samples (n = 396) from a prospective, observational cohort of 59 renal transplant patients with surveillance or indication biopsies were assayed for 133 unique metabolites by quantitative mass spectrometry. Samples were classified according to Banff criteria for AMR and partial least squares discriminant analysis was used to identify associated changes in metabolite patterns by creating a composite index based on all 133 metabolites.

Results: Urine samples of patients with (n = 40) and without AMR (n = 278) were analyzed and a classifier for AMR was identified (area under receiver operating characteristic curve = 0.84; 95% confidence interval, 0.77-0.91; P = 0.006). Application of the classifier to "indeterminate" samples (samples that partially fulfilled Banff criteria for AMR; n = 65) yielded an AMR score of 0.19 ± 0.15, intermediate between scores for AMR and No AMR (0.28 ± 0.14 and 0.10 ± 0.13 respectively, P ≤ 0.001). The AMR score was associated with the presence of donor-specific antibodies, biopsy indication, Banff ct, t, ah and cg scores, and retained accuracy when applied to subclinical cases (creatinine, <25% increase from baseline) or had minimal or no transplant glomerulopathy (Banff cg0-1). Exploratory classifiers that segregated samples based on concurrent T cell-mediated rejection (TCMR) identified overlapping metabolite signatures between AMR and TCMR, suggesting similar pathophysiology of tissue injury.

Conclusions: These preliminary findings identify a urine metabolic classifier for AMR. Independent validation is needed to verify its utility for accurate, noninvasive AMR detection.
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http://dx.doi.org/10.1097/TP.0000000000001662DOI Listing
October 2017

Atypical cells in a voided urine cytology specimen in a renal transplant recipient.

Diagn Cytopathol 2017 Jan 16;45(1):69-72. Epub 2016 Sep 16.

Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.

Voided urine is routinely collected from renal transplant patients to screen for polyomavirus. In rare cases, atypical lymphoid cells can be detected in voided urine and raise the suspicion of post-transplant lymphoproliferative disorder (PTLD). However, further immunohistochemistry of the cell block and flow cytometry is frequently limited by the low cellularity and poor preservation of voided urine. Therefore, PTLD of the renal allograft is usually diagnosed from tissue biopsy or nephrectomy specimens. Herein, we report a rare case of atypical cells in a voided urine cytology specimen from a kidney transplant recipient. Needle core biopsy of the renal allograft showed monomorphic PTLD. Diagn. Cytopathol. 2017;45:69-72. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/dc.23602DOI Listing
January 2017

Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10.

Transplant Direct 2016 Jun 19;2(6):e78. Epub 2016 May 19.

Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.

Background: The goal of this study was to characterize urinary metabolomics for the noninvasive detection of cellular inflammation and to determine if adding urinary chemokine ligand 10 (CXCL10) improves the overall diagnostic discrimination.

Methods: Urines (n = 137) were obtained before biopsy in 113 patients with no (n = 66), mild (borderline or subclinical; n = 58), or severe (clinical; n = 13) rejection from a prospective cohort of adult renal transplant patients (n = 113). Targeted, quantitative metabolomics was performed with direct flow injection tandem mass spectrometry using multiple reaction monitoring (ABI 4000 Q-Trap). Urine CXCL10 was measured by enzyme-linked immunosorbent assay. A projection on latent structures discriminant analysis was performed and validated using leave-one-out cross-validation, and an optimal 2-component model developed. Chemokine ligand 10 area under the curve (AUC) was determined and net reclassification index and integrated discrimination index analyses were performed.

Results: PLS2 demonstrated that urinary metabolites moderately discriminated the 3 groups (Cohen κ, 0.601; 95% confidence interval [95% CI], 0.46-0.74; P < 0.001). Using binary classifiers, urinary metabolites and CXCL10 demonstrated an AUC of 0.81 (95% CI, 0.74-0.88) and 0.76 (95% CI, 0.68-0.84), respectively, and a combined AUC of 0.84 (95% CI, 0.78-0.91) for detecting alloimmune inflammation that was improved by net reclassification index and integrated discrimination index analyses. Urinary CXCL10 was the best univariate discriminator, followed by acylcarnitines and hexose.

Conclusions: Urinary metabolomics can noninvasively discriminate noninflamed renal allografts from those with subclinical and clinical inflammation, and the addition of urine CXCL10 had a modest but significant effect on overall diagnostic performance. These data suggest that urinary metabolomics and CXCL10 may be useful for noninvasive monitoring of alloimmune inflammation in renal transplant patients.
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http://dx.doi.org/10.1097/TXD.0000000000000589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946516PMC
June 2016

Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury.

Transplantation 2016 Mar;100(3):648-54

1 Section of Nephrology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.2 Manitoba Centre for Proteomics and Systems Biology, University of Manitoba and Health Sciences Centre, Winnipeg, Manitoba, Canada.3 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.4 Institute for Technical Biochemistry, University of Stuttgart, Stuttgart, Germany.5 University of Manitoba, Winnipeg, Manitoba, Canada.6 Cardiac Sciences Program, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada.7 Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: The urinary CXC chemokine ligand (CXCL)10 detects renal transplant inflammation noninvasively, but has limited sensitivity and specificity. In this study, we performed urinary proteomic analysis to identify novel biomarkers that may improve the diagnostic performance of urinary CXCL10 for detecting alloimmune inflammation in renal transplant patients.

Methods: In preliminary studies, adult renal transplant patients with normal histology (n = 5), interstitial fibrosis and tubular atrophy (n = 6), subclinical (n = 6) and clinical rejection (n = 6), underwent in-depth urine protein compositional analysis with LC-MS/MS, and matrix metalloproteinase-7 (MMP7) were identified as a potential candidate for the diagnosis of renal allograft inflammation. Urine MMP7 performance was then studied in a larger, prospective adult renal transplant population (n = 148 urines from n = 133 patients) with matched surveillance/indication biopsies. The diagnostic performance of urinary MMP7 and CXCL10 in combination was next evaluated using concordance (C-) statistics, net reclassification improvement and integrated discrimination improvement indices, to determine whether it was better than CXCL10 alone.

Results: Urinary MMP7:creatinine (Cr) was lower in normal transplants compared to those with inflammation: glomerulonephritis (P = 0.009), viral nephropathies (P = 0.002), interstitial fibrosis and tubular atrophy and inflammation (P = 0.04), borderline (P = 0.08), subclinical (P = 0.01) and clinical rejection (P = 0.0006), and acute tubular necrosis (P < 0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished noninflamed from inflamed biopsies (area under the curve, 0.74 and 0.70, respectively). The addition of urinary MMP7:Cr to CXCL10:Cr improved the diagnostic performance for subclinical and clinical inflammation/injury by integrated discrimination improvement (P = 0.002) and net reclassification improvement (P = 0.006) analyses.

Conclusions: Urinary MMP7:Cr improves the overall diagnostic performance of urinary CXCL10:Cr for distinguishing normal histology from subclinical and clinical inflammation/injury, but not subclinical inflammation alone.
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http://dx.doi.org/10.1097/TP.0000000000000867DOI Listing
March 2016

The perils of immunosuppression minimization: lessons from protocol biopsies of renal allografts.

Curr Opin Nephrol Hypertens 2015 Nov;24(6):582-6

aDepartment of Internal Medicine bDepartment of Pathology, University of Manitoba, Manitoba, Canada.

Purpose Of Review: To emphasize the pathogenicity of subclinical cellular inflammation in renal transplant recipients, and its relation to poor graft outcomes and the development of de-novo donor-specific antibody (DSA).

Recent Findings: Protocol biopsies have identified the gene signatures of innate and adaptive immunity in patients with minimal inflammation that correlate with the subsequent development of graft interstitial fibrosis, transplant glomerulopathy and antibody-mediated rejection. The risks of immunosuppression minimization, especially in HLA mismatched donor-recipient pairs, are highlighted.

Summary: The major cause of renal allograft loss is immunological and a contributor to this is the minimization of immunosuppression. The prevention of premature graft loss requires better matching of class II HLA antigens, the targets of de-novo DSA, and monitoring for subclinical inflammation rejection with protocol biopsies or urine chemokines.
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http://dx.doi.org/10.1097/MNH.0000000000000170DOI Listing
November 2015

Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

J Am Soc Nephrol 2015 Dec 29;26(12):3114-22. Epub 2015 Apr 29.

Department of Medicine and Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York;

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.
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http://dx.doi.org/10.1681/ASN.2014121234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657844PMC
December 2015