Publications by authors named "Kim Solez"

34 Publications

Reinnovating nephrology-a call to action.

Kidney Int 2021 01;99(1):5-8

Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.08.032DOI Listing
January 2021

Immune checkpoint inhibitor-induced granulomatosis with polyangiitis.

Rheumatology (Oxford) 2020 Dec 25. Epub 2020 Dec 25.

Department of Rheumatology, University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1093/rheumatology/keaa818DOI 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

Banff Digital Pathology Working Group: Going digital in transplant pathology.

Am J Transplant 2020 09 19;20(9):2392-2399. Epub 2020 Apr 19.

University of Alberta, Edmonton, Canada.

The Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27, 2019, held in Pittsburgh, Pennsylvania. At the meeting, the 14th Banff Conference, presentations directly and peripherally related to the topic of "digital pathology" were presented; and discussions before, during, and after the meeting have resulted in a list of issues to address for the DPWG. Included are practice standardization, integrative approaches for study classification, scoring of histologic parameters (eg, interstitial fibrosis and tubular atrophy and inflammation), algorithm classification, and precision diagnosis (eg, molecular pathways and therapeutics). Since the meeting, a survey with international participation of mostly pathologists (81%) was conducted, showing that whole slide imaging is available at the majority of centers (71%) but that artificial intelligence (AI)/machine learning was only used in ≈12% of centers, with a wide variety of programs/algorithms employed. Digitalization is not just an end in itself. It also is a necessary precondition for AI and other approaches. Discussions at the meeting and the survey highlight the unmet need for a Banff DPWG and point the way toward future contributions that can be made.
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http://dx.doi.org/10.1111/ajt.15850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496838PMC
September 2020

A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.

Transplantation 2018 11;102(11):1795-1814

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward.
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http://dx.doi.org/10.1097/TP.0000000000002366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597974PMC
November 2018

The Human Cell Atlas Project by the numbers: Relationship to the Banff Classification.

Am J Transplant 2018 07 21;18(7):1830. Epub 2018 Apr 21.

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

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http://dx.doi.org/10.1111/ajt.14757DOI Listing
July 2018

Interobserver agreement for post mortem renal histopathology and diagnosis of acute tubular necrosis in critically ill patients.

Crit Care Resusc 2017 Dec;19(4):337-343

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

Background: The renal histopathology of critically ill patients dying with acute kidney injury (AKI) in intensive care units of high income countries remains uncertain.

Methods: Retrospective observational assessment of interobserver agreement in the reporting of renal post mortem histopathology, and the ability of pathologists blinded to the clinical context to independently identify the presence of pre-mortem AKI from digital images of histological sections from 34 critically ill patients dying in teaching hospitals in Australia and Canada.

Results: We identified a heterogeneous cohort with a median age of 65 years (interquartile range [IQR], 56.5-77), APACHE II score of 27 (IQR, 19-33), and sepsis as the most common admission diagnosis (12/34; 35%). The most common proximate causes of death were cardiovascular (19/34; 56%) and respiratory (7/34; 21%) failure. AKI was common, with 23 patients (68%) developing RIFLE-F AKI, and 21 patients (62%) receiving renal replacement therapy. Structured reporting for tubular inflammation showed excellent agreement (kappa = 1), but no other subdomain demonstrated better than moderate agreement (kappa < 0.6). Only fair agreement (55.9% of cases; kappa = 0.23) was demonstrated on the diagnosis of moderate to severe acute tubular necrosis (ATN). Pathologist A predicted RIFLE-I or worse AKI with the diagnosis of ATN, with an overall accuracy of 61.8%; pathologist B predicted AKI with an accuracy of 35.3%.

Conclusions: Post mortem assessment of the renal histopathology in critically ill patients is neither robust nor reproducible; independent pathologists agree poorly on the diagnosis of ATN, and their structural assessment appears dissociated from ante-mortem renal function.
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December 2017

Foreword.

Transplant Proc 2017 12;49(10):2239

Board of the Catalan Transplantation Society and Foundation.

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http://dx.doi.org/10.1016/j.transproceed.2017.10.012DOI Listing
December 2017

Kim Solez, Edmonton, Alberta, Canada Banff: A Unique Start Setting Standards for Consensus Conferences.

Authors:
Kim Solez

Transplantation 2017 10;101(10):2264-2266

1 Department of Laboratory Medicine and Pathology, University of Albert, Edmonton, AB.

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http://dx.doi.org/10.1097/TP.0000000000001901DOI Listing
October 2017

Multibiomarker Article Gives a Taste of What the Era of Regenerative Medicine/Tissue Engineering Pathology Will Be Like.

Authors:
Kim Solez

Crit Care Med 2015 Dec;43(12):e599-600

Department of Pathology, University of Alberta, Edmonton, AB, Canada.

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http://dx.doi.org/10.1097/CCM.0000000000001293DOI Listing
December 2015

Bridging the gap between the technological singularity and mainstream medicine: highlighting a course on technology and the future of medicine.

Glob J Health Sci 2013 Sep 9;5(6):112-25. Epub 2013 Sep 9.

University of Alberta.

The "technological singularity" is defined as that putative point in time forecasted to occur in the mid twenty-first century when machines will become smarter than humans, leading humans and machines to merge. It is hypothesized that this event will have a profound influence on medicine and population health. This work describes a new course on Technology and the Future of Medicine developed by a diverse, multi-disciplinary group of faculty members at a Canadian university. The course began as a continuous professional learning course and was later established as a recognized graduate course. We describe the philosophy of the course, the barriers encountered in course development, and some of the idiosyncratic solutions that were developed to overcome these, including the use of YouTube audience retention analytics. We hope that this report might provide a useful template for other institutions attempting to set up similar programs.
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http://dx.doi.org/10.5539/gjhs.v5n6p112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776857PMC
September 2013

Thalidomide suppresses inflammation in adenine-induced CKD with uraemia in mice.

Nephrol Dial Transplant 2013 May 22;28(5):1140-9. Epub 2013 Jan 22.

Laboratory of Cellular and Molecular Nephrology, Division of Nephrology, University of São Paulo, São Paulo, Brazil.

Background: Persistent systemic inflammation has been widely recognized in patients with chronic kidney disease (CKD), and is associated with increased risk of morbidity and mortality. Intervention therapies aiming for the blockade of inflammatory cytokines are considered attractive approaches for CKD patients with signs of chronic inflammation. In this context, thalidomide, due to its potent anti-inflammatory and immunomodulatory properties, may represent an alternative strategy of treatment. In the present study, we developed an experimental model of CKD with uraemia in mice, induced by a diet rich in adenine, which causes progressive renal dysfunction, resembling the human uraemic features. Inflammatory parameters were analysed in this model of CKD and the potential beneficial effects of thalidomide as an anti-inflammatory drug was also investigated.

Methods: C57/BL-6 mice were fed with an adenine-containing diet during a period of 6 weeks. Thirty mice were divided into three groups: Control group (animals receiving normal diet), ADE group (mice receiving adenine-containing diet) and ADE + TLD group (CKD mice receiving thalidomide, 30 mg/kg/day, by gavage). Besides biochemical and histopathological changes, local and systemic inflammatory parameters were also analysed, including expression of cytokines interleukin (IL)-1β, tumour necrosis factor-α, IL-6, IL-4 and IL-10 in kidney samples by real-time RT-PCR and quantification of serum levels of cytokines. Finally, the electrophoretic mobility shift assay (EMSA) for NF-κB was also examined.

Results: Adenine-fed mice developed advanced CKD characterized by a marked increase in serum urea, creatinine, phosphorus and intact parathyroid hormone (iPTH) levels. In addition, histological changes of tubulointerstitial injury, characterized by deposition of crystals in the kidney, accompanied by tubular dilatation, degeneration of proximal tubular epithelium with loss of the brush border, inflammatory cellular infiltration, foreign-body granuloma formation and interstitial fibrosis were also evident. By immunohistochemistry, Mac-2- and α-SMA-positive cells were identified in the tubulointerstitial compartment. Treatment with thalidomide significantly reduced serum urea, creatinine, phosphorus and iPTH levels and protected against tubulointerstitial injury. Local and systemic inflammation in the mice model of adenine-induced CKD was confirmed by the findings of significantly high expression of cytokine mRNA levels and NF-κB activation in the kidney tissue as well as marked increased serum levels of inflammatory cytokines. Thalidomide treatment significantly reduced gene expression of these cytokines and the activation of the NF-κB in the renal tissue and the circulating levels of cytokines.

Conclusions: Dietary adenine caused advanced CKD with uraemia in mice providing a useful experimental model to study molecular and morphological changes associated with this disease. The negative impact of inflammation in this CKD model was overcome by the marked anti-inflammatory effects of thalidomide, promoting renal protection.
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http://dx.doi.org/10.1093/ndt/gfs569DOI Listing
May 2013

The Banff classification revisited.

Kidney Int 2013 Feb 12;83(2):201-6. Epub 2012 Dec 12.

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

From small beginnings in 1991, the Banff working classification of renal allograft pathology has grown to be a major force for setting standards in renal transplant pathology, and is widely used in international clinical trials of new antirejection agents. The meeting, classification, and consensus process have unique history, and look poised to continue for another several decades as the embodiment of the process for setting global standards in pathology. The Banff meetings have expanded from renal allograft pathology to most other areas of solid organ transplantation, and increasingly incorporate international working groups, so that productive collaborative activity is ongoing, creating an important dynamic process enhancing clinical success in transplantation. On the other hand, despite the successes of the working classifications and ongoing collaborative efforts, there are limitations in this and other pathological classifications, related to potential for sampling error, issues of reproducibility when implemented globally, and lack of formal incorporation of morphometry and molecular and genomics approaches. Some of these problems cannot be overcome within the realm of traditional histopathology, and will only be solved when the classification is able to confidently embrace genomics and molecular medicine parameters for all common diagnoses. The smooth integration of these newer technologies with traditional histopathology is one of the great challenges for the future.
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http://dx.doi.org/10.1038/ki.2012.395DOI Listing
February 2013

Multifaceted support for a new medical school in Nepal devoted to rural health by a Canadian Faculty of Medicine and Dentistry.

Glob J Health Sci 2012 Sep 10;4(6):109-18. Epub 2012 Sep 10.

University of Alberta, Alberta, Canada.

Nepal and Alberta are literally a world apart. Yet they share a common problem of restricted access to health services in remote and rural areas. In Nepal, urban-rural disparities were one of the main issues in the recent civil war, which ended in 2006. In response to the need for improved health equity in Nepal a dedicated group of Nepali physicians began planning the Patan Academy of Health Sciences (PAHS), a new health sciences university dedicated to the education of rural health providers in the early 2000s. Beginning with a medical school the Patan Academy of Health Sciences uses international help to plan, deliver and assess its curriculum. PAHS developed an International Advisory Board (IAB) attracting international help using a model of broad, intentional recruitment and then on individuals' natural attraction to a clear mission of peace-making through health equity. Such a model provides for flexible recruitment of globally diverse experts, though it risks a lack of coordination. Until recently, the PAHS IAB has not enjoyed significant or formal support from any single international institution. However, an increasing number of the international consultants recruited by PAHS to its International Advisory Board are from the University of Alberta in Edmonton, Alberta, Canada (UAlberta). The number of UAlberta Faculty of Medicine and Dentistry members involved in the project has risen to fifteen, providing a critical mass for a coordinated effort to leverage institutional support for this partnership. This paper describes the organic growth of the UAlberta group supporting PAHS, and the ways in which it supports a sister institution in a developing nation.
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http://dx.doi.org/10.5539/gjhs.v4n6p109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777003PMC
September 2012

Superiority of virtual microscopy versus light microscopy in transplantation pathology.

Clin Transplant 2012 Mar-Apr;26(2):336-44. Epub 2011 Sep 29.

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

Virtual microscopy has begun to change conventional pathology practice. We tested the reliability of this new technology in transplantation pathology. We studied 40 kidney transplant biopsies for cause and compared reproducibility of Banff scores using virtual slides versus glass slides. Three glass slides per biopsy were scanned as high-resolution digital slides using Aperio ScanScope. Three pathologists independently reviewed the biopsies: twice by glass slides and twice by virtual slides. Eleven histopathological lesions were scored and used to construct diagnosis according to Banff criteria. The intra-observer reproducibility of Banff scores was substantially good using either virtual slides or glass slides (mean κ: 0.69 vs. 0.64, p>0.05). The inter-observer reproducibility of Banff scores was better in virtual slides than in glass slides (mean κ: 0.42 vs. 0.28, p<0.001). Among the lesions, transplant glomerulopathy scoring by virtual slides showed the highest inter-observer reproducibility, with a similar accuracy to glass slides. The agreement for acute rejection between virtual and glass slides was not different from the agreement between two readings of glass slides. Thus, virtual microscopy is a reliable and more reproducible technology and has several advantages over glass slides, e.g., accessibility via internet, no fading. We recommend virtual microscopy for transplant diagnostics, including utilization for clinical trials.
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http://dx.doi.org/10.1111/j.1399-0012.2011.01506.xDOI Listing
August 2012

Assessment of kidney organ quality and prediction of outcome at time of transplantation.

Semin Immunopathol 2011 Mar 28;33(2):185-99. Epub 2011 Jan 28.

Division of Nephrology and Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.

The critical importance of donor organ quality, i.e., number of surviving nephrons, ability to withstand injury, and capacity for repair in determining short- and long-term outcomes is becoming increasingly clear. This review provides an overview of studies to assess donor kidney quality and subsequent transplant outcomes based on clinical pathology and transcriptome-based variables available at time of transplantation. Prediction scores using clinical variables function when applied to large data sets but perform poorly for the individual patient. Histopathology findings in pre-implantation or post-reperfusion biopsies help to assess structural integrity of the donor kidney, provide information on pre-existing donor disease, and can serve as a baseline for tracking changes over time. However, more validated approaches of analysis and prospective studies are needed to reduce the number of discarded organs, improve allocation, and allow prediction of outcomes. Molecular profiling detects changes not seen by morphology or captured by clinical markers. In particular, molecular profiles provide a quantitative measurement of inflammatory burden or immune activation and reflect coordinated changes in pathways associated with injury and repair. However, description of transcriptome patterns is not an end in itself. The identification of predictive gene sets and the application to an individualized patient management needs the integration of clinical and pathology-based variables, as well as more objective reference markers of transplant function, post-transplant events, and long-term outcomes.
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http://dx.doi.org/10.1007/s00281-011-0248-xDOI Listing
March 2011

The prognostic utility of deceased donor implantation biopsy in determining function and graft survival after kidney transplantation.

Transplantation 2010 Mar;89(5):559-66

Divisions of Nephrology, University of Alberta, Edmonton, Alberta, Canada.

Background: Uncertainty remains in the prognostic utility of biopsies of deceased donor kidneys in predicting graft outcomes.

Methods: We examined implantation biopsies for 730 kidney transplant recipients from 491 deceased donors from 1990 to 2004. The median follow-up time was 5.1 years. Of the 730 transplants, 633 (86.7%) had implantation biopsies (wedge 89.1%). Of these 633, 541 (85.5%) could be assessed for % glomerulosclerosis (GS), interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and fibrous intimal thickening. Independent risk factors for delayed graft function include regraft, longer cold ischemia time, and DR mismatch, but not donor age. Independent risk factors for worse function at 6 months include regraft, older donor and recipient, female donor and recipient, and rejection. Independent risk factors of graft failure include regraft, older donor age, male recipient, and rejection.

Results: Of the histologic scores, arteriolar hyalinosis was independently associated with delayed graft function and graft loss, whereas fibrous intimal thickening was associated with decreased 6-month renal function. Importantly, the degree of GS was not independently associated with outcomes.

Conclusions: Therefore, although biopsy evidences of vascular pathologic condition, kidney may contribute meaningfully to the assessment of donor quality but the degree of GS does not.
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http://dx.doi.org/10.1097/TP.0b013e3181ca7e9bDOI Listing
March 2010

Technofuturism in pathology.

Authors:
Kim Solez

Curr Opin Organ Transplant 2010 Feb;15(1)

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http://dx.doi.org/10.1097/MOT.0b013e328334e778DOI Listing
February 2010

History of the Banff classification of allograft pathology as it approaches its 20th year.

Authors:
Kim Solez

Curr Opin Organ Transplant 2010 Feb;15(1):49-51

Department of Pathology, University of Alberta, Edmonton, Canada.

Purpose Of Review: To revisit the history and main defining characteristics of the Banff classification.

Recent Findings: From small beginnings in 1991 the Banff classification of renal allograft pathology has grown to be the major standard setting force in renal transplant pathology and in international clinical trials of new antirejection agents. The meeting and classification has unique history, consensus generation mechanisms, funding, and tradition, and looks poised to continue for at least another 20 years. The Banff meetings also deal with setting standards for most other areas of solid organ transplantation and increasingly incorporate training courses and working groups so the activity never stops.

Summary: The Banff meeting has gone from being just another meeting to becoming the embodiment of the global standard, The Banff Classification, by which we determine the presence of rejection and other important disease conditions in the transplanted organ. It is crucial for patient care and crucial for clinical trials of new therapies that it remains updated and modern, an important dynamic yardstick against which we measure clinical success.
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http://dx.doi.org/10.1097/MOT.0b013e328334fedbDOI Listing
February 2010

Biomarkers for early and late stage chronic allograft nephropathy by proteogenomic profiling of peripheral blood.

PLoS One 2009 Jul 10;4(7):e6212. Epub 2009 Jul 10.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Background: Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression.

Methods: We used DNA microarrays, tandem mass spectroscopy proteomics and bioinformatics to identify genomic and proteomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n = 77 total) of kidney transplant patients with biopsy-documented histology.

Findings: Gene expression profiles reveal over 2400 genes for mild CAN, and over 700 for moderate/severe CAN. A consensus analysis reveals 393 (mild) and 63 (moderate/severe) final candidates as CAN markers with predictive accuracy of 80% (mild) and 92% (moderate/severe). Proteomic profiles show over 500 candidates each, for both stages of CAN including 302 proteins unique to mild and 509 unique to moderate/severe CAN.

Conclusions: This study identifies several unique signatures of transcript and protein biomarkers with high predictive accuracies for mild and moderate/severe CAN, the most common cause of late allograft failure. These biomarkers are the necessary first step to a proteogenomic classification of CAN based on peripheral blood profiling and will be the targets of a prospective clinical validation study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006212PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703807PMC
July 2009

The case mid R: A kidney transplant presenting with acute renal failure and mass.

Kidney Int 2009 Mar;75(5):565-6

Department of Laboratory Medicine and Pathology, Walter C Mackenzie Health Sciences Center, University of Alberta Hospital, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1038/ki.2008.548DOI Listing
March 2009

Antibody-mediated rejection with a striking interstitial monocyte/macrophage infiltration in a renal allograft under FTY720 treatment.

Am J Kidney Dis 2008 Jan;51(1):127-30

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

FTY720, a novel immunomodulator, causes rapid temporary depletion of peripheral-blood lymphocytes, inducing their sequestration in secondary lymphoid organs. FTY720 is effective in animal models of transplantation and is under evaluation for use in human transplantation. We report a 48-year-old renal transplant recipient who developed acute antibody-mediated rejection under a high-dose FTY720 (5 mg/d), low-dose cyclosporine A, and prednisone treatment protocol. A T-cell antihuman globulin and National Institutes of Health extended B-cell cross-match with donor cells were negative before transplantation. At 10 weeks posttransplantation, serum creatinine level increased and a renal biopsy showed a striking interstitial CD68(+) monocyte/macrophage infiltration with C4d staining of peritubular capillaries. Flow panel reactive antibody levels were positive in the recipient's serum for class I (9%) and class II (75%). The positive panel reactive antibody levels and presence of C4d in peritubular capillaries justified the diagnosis of antibody-mediated rejection. However, the presence of macrophage-rich interstitial infiltrate suggested a contribution of cellular rejection. The morphological characteristic of rejection with a striking interstitial CD68(+) monocyte/macrophage infiltration with paucity of T cells is very unusual and may reflect a unique effect of FTY720 therapy.
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http://dx.doi.org/10.1053/j.ajkd.2007.08.023DOI Listing
January 2008

Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.

Transplantation 2007 Apr;83(7):883-92

Transplant Center/Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Background: We report the 5-year outcomes from a randomized prospective trial in primary adult renal allograft recipients, designed to evaluate calcineurin inhibitor (CNI)-free immunosuppression on kidney transplant function.

Methods: Sixty-one patients were randomized to either sirolimus (n=31) or cyclosporine (n=30) after basiliximab induction and mycophenolate mofetil (MMF) with steroids. Sirolimus was concentration controlled at 10-12 ng/mL for at least 6 months.

Results: After 5 years, sirolimus-MMF-steroids compared to cyclosporine-MMF-steroids provides similar patient survival (87.1 vs. 90%, P=0.681), acute rejection rates (12.9 vs. 23.3%, P=0.22), total cholesterol (209.1 vs. 204.3 mg/dL, P=0.973), urine protein/creatinine ratios (0.398 vs. 0.478 mg/dL, P=0.72), and overall medical and surgical morbidity (P=NS). Although unadjusted patient survival was similar, sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs. 76.7%, P=0.0265), higher glomerular filtration rate (GFR) by the abbreviated Modified Diet in Renal Disease (66.7 vs. 50.7 cc/min, P=0.0075), and fewer graft losses from chronic allograft nephropathy. The Banff chronic scores at two years were strong predictors of 5-year GFR. At 5 years, there were six de novo (three solid organ, three skin) cancers in the CNI group and only two de novo (one skin, one leukemia, no solid organ) cancers in the sirolimus group (P=NS).

Conclusions: This study of low to moderate risk patients demonstrates that excellent 5-year kidney transplant outcomes can be achieved without CNI drugs, when therapeutic drug monitoring of sirolimus is employed. The application of CNI drug avoidance protocols to high-risk recipients (retransplants, highly sensitized, etc.), extrarenal allograft recipients, or alternative drug regimens such as steroid or MMF elimination should be subjected to controlled trials.
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http://dx.doi.org/10.1097/01.tp.0000258586.52777.4cDOI Listing
April 2007

Recurrence of hemolytic-uremic syndrome following live related renal transplantation.

Arch Iran Med 2006 Apr;9(2):170-2

Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran.

There is a significant risk of disease recurrence in patients with diarrhea-negative hemolyticuremic syndrome undergoing renal transplantation. Considering the low frequency of hemolyticuremic syndrome among adults with end-stage renal disease, only a few reports are available on the outcome of these patients after renal transplantation. It has been suggested, though not proven, that living related transplant recipients are at increased risk of recurrence of hemolyticuremic syndrome. We report a 23-year-old woman with end-stage renal disease, owing to postpartum hemolyticuremic syndrome and the recurrence of the disease following live related renal transplant. Investigators believe that some cases of atypical hemolytic-uremic syndrome are familial and related donors may have a genetic susceptibility to develop hemolytic-uremic syndrome. In addition, recurrence of hemolytic-uremic syndrome in the allograft is associated with a very poor prognosis. Therefore, at present, many clinicians are reluctant to recommend live related transplantation in any forms of diarrhea-negative hemolytic-uremic syndrome.
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April 2006

Costimulation blockade with belatacept in renal transplantation.

N Engl J Med 2005 Aug;353(8):770-81

University of California, San Francisco, San Francisco, USA.

Background: Renal transplantation is the standard of care for patients with end-stage renal disease. Although maintenance immunosuppression with calcineurin inhibitors yields excellent one-year survival, it is associated over the long term with high rates of death and graft loss, owing in part to the adverse renal, cardiovascular, and metabolic effects of these agents. The use of potentially less toxic agents, such as belatacept, a selective blocker of T-cell activation, may improve outcomes.

Methods: We randomly assigned renal-transplant recipients to receive an intensive or a less-intensive regimen of belatacept or cyclosporine. All patients received induction therapy with basiliximab, mycophenolate mofetil, and corticosteroids. The primary objective was to demonstrate the noninferiority of belatacept over cyclosporine in the incidence of acute rejection at six months (with an upper bound of the 95 percent confidence interval around the treatment difference of less than 20 percent).

Results: At six months, the incidence of acute rejection was similar among the groups: 7 percent for intensive belatacept, 6 percent for less-intensive belatacept, and 8 percent for cyclosporine. At 12 months, the glomerular filtration rate was significantly higher with both intensive and less-intensive belatacept than it was with cyclosporine (66.3, 62.1, and 53.5 ml per minute per 1.73 m2, respectively), and chronic allograft nephropathy was less common with both regimens of belatacept than with cyclosporine (29 percent, 20 percent, and 44 percent, respectively). Lipid levels and blood-pressure values were similar or slightly lower in the belatacept groups, despite the greater use of lipid-lowering and antihypertensive medications in the cyclosporine group.

Conclusions: Belatacept, an investigational selective costimulation blocker, did not appear to be inferior to cyclosporine as a means of preventing acute rejection after renal transplantation. Belatacept may preserve the glomerular filtration rate and reduce the rate of chronic allograft nephropathy.
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http://dx.doi.org/10.1056/NEJMoa050085DOI Listing
August 2005

Electronic strategies for information and research: cyberNephrology/cyberMedicine in the emerging world.

Kidney Int Suppl 2005 Sep(98):S89-94

The National Kidney Foundation cyberNephrology Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

Communication and medicine have evolved together. Internet resources now provide an unprecedented opportunity to provide health assistance to the developing world. The International Society of Nephrology Informatics Commission and National Kidney Foundation cyberNephrology initiative (http://www.cybernephrology.org) have created e-mail discussion groups (e.g., NEPHROL, NEPHKIDS, and so forth) and online texts and web resources (e.g., the Schrier Atlas: http://www.kidneyatlas.org) that are, in many respects, ahead of other areas of medicine. On the other hand, nephrology is quite behind in its embrace of some specific communications initiatives that could benefit emerging nations: the Health InterNetwork Access to Research Initiative program, which provides free full-text access to medical journals and books in poorer countries; the Global Health Network Supercourse, which provides specially designed online lectures for the developing world; and Internet2/Abilene and similar research networks around the world, which provide reliable, guaranteed bandwidth for high-quality Internet videoconferencing as an alternative to face-to-face lectures and meetings. The intent of many educational ventures in nephrology, particularly in the clinical practice guideline realm (National Kidney Foundation Kidney Disease Outcomes Quality Initiative, Kidney Disease Improving Global Outcomes, and so forth), is not just to disseminate information but to change human behavior: physician practice and referral patterns, patient compliance, and so forth. Concepts from the worlds of marketing and entertainment, where the science of changing human behavior is highly evolved, can be used to create high-impact, educational offerings to promote health. They can also be highly beneficial to share Internet educational innovations and future vision across boundaries of medical specialties, which is part of the intent of the cyberMedicine joint venture (http://www.cyber-medicine.org).
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http://dx.doi.org/10.1111/j.1523-1755.2005.09817.xDOI Listing
September 2005

Prevention of chronic kidney and vascular disease: toward global health equity--the Bellagio 2004 Declaration.

Kidney Int Suppl 2005 Sep(98):S1-6

Massey College, Ontario, Toronto, Canada.

Chronic kidney disease (CKD) not only reflects target organ injury in systemic vascular disease in the general population and in association with diabetes, hypertension, and smoking, but it is recognized as one of the major risk factors in the pathogenesis and outcome of cardiovascular disease. Recent surveys have revealed that the prevalence of CKD, particularly the hidden mild form (mildly elevated levels of serum creatinine or urinary albumin excretion), is surprisingly high in the general population. In recent years, the global epidemic of type 2 diabetes has led to an alarming increase in the number of patients with CKD. Most patients with CKD (over 50 million individuals worldwide) succumb to cardiovascular events, while each year over 1 million develop end-stage renal failure, which requires costly treatment and in many countries of the world, unaffordable renal replacement therapy by chronic dialysis or renal transplantation. Alarmed by the immense challenge to human morbidity and the economic burden of CKD and ensuing systemic cardiovascular disease, the International Society of Nephrology convened a multidisciplinary group of expert physicians and public health leaders from around the world to develop strategies to delay and avert this bleak future by effective prevention of CKD based on awareness, early detection, and effective treatment.
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http://dx.doi.org/10.1111/j.1523-1755.2005.09800.xDOI Listing
September 2005

De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years.

Am J Transplant 2004 Nov;4(11):1776-85

Section of Renal Transplantation, Transplant Center, and Allogen Laboratories, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.

We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure and gene expression. Sixty-one kidney recipients treated with basiliximab mycophenolate mofetil (MMF) and prednisone (P) were randomly assigned to concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Comparing sirolimus/MMF/P to cyclosporine/MMF/P there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dL; p = 0.008), higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 mL/min; p = 0.008), iothalamate GFR (60.6 vs. 49.2 mL/min; p = 0.018) and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p = 0.013). Regression analysis of calculated GFRs from 1 to 36 months yielded a positive slope for sirolimus of 3.36 mL/min/year, and a negative slope for cyclosporine of -1.58 mL/min/year (p = 0.008). Gene expression profiles from kidneys with higher Banff chronic allograft nephropathy (CAN) scores confirmed significant up-regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. At 2 years the sirolimus-treated recipients have better renal function, a diminished prevalence of CAN and down-regulated expression of genes responsible for progression of CAN. All may provide for an alternative natural history with improved graft survival.
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http://dx.doi.org/10.1111/j.1600-6143.2004.00627.xDOI Listing
November 2004

Banff 2003 meeting report: new diagnostic insights and standards.

Am J Transplant 2004 Oct;4(10):1562-6

Department of Pathology, The Johns Hopkins University School of Medicine, USA.

The Seventh Banff Conference on Allograft Pathology was held June 14-18, 2003 in Aberdeen, Scotland representing the latest iteration of the international consensus meeting, which develops worldwide standards for interpretation of allograft biopsies. The meeting is an important force behind standardized slide interpretation to strengthen endpoints in international clinical trials. Of participants polled 87% reported that they would alter clinical practice as a direct consequence of the meeting and its content. Advances were made in many areas including tubulitis mechanisms, real-time polymerase chain reaction (PCR) gene analysis and microarrays in rejection diagnosis, tolerance/accommodation/immunomodulation, the role of monocytes and macrophages in rejection and C4d as a marker for antibody-mediated rejection. A provisional scoring system for peritubular capillary inflammatory cell accumulation in antibody-mediated rejection was presented for testing, as well as plans for a nephrectomy study to determine specificity of vascular lesions of rejection. Future meetings are planned for 2005 (Edmonton), 2007 and 2009, with active ongoing Internet discussion between meetings.
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http://dx.doi.org/10.1111/j.1600-6143.2004.00585.xDOI Listing
October 2004

Peritubular capillary changes and C4d deposits are associated with transplant glomerulopathy but not IgA nephropathy.

Am J Transplant 2004 Jan;4(1):124-9

Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada.

We examined our renal transplant population for glomerular diseases demonstrated on biopsy between January 1993 and April 2002, focusing on transplant glomerulopathy (TGP). Of 1156 patients followed in our clinics during this period, glomerular disease was diagnosed in 132 cases (11.4%). Glomerulonephritis was diagnosed in 86 transplants (7.4%), with IgA nephropathy (IgAN) being the commonest diagnosis [32 cases (2.8%)]. Thirty-one cases (2.7%) of biopsy-proven TGP were analyzed for associated factors compared with 27 cases (2.3%) of recurrent IgAN. Transplant glomerulopathy was less frequent with mycophenolate mofetil (MMF) and/or tacrolimus, whereas recurrent IgAN showed no such tendency (P= 0.02). Peritubular capillary (PTC) C4d deposition was observed in six of 24 cases (25%) with TGP but none with recurrent IgAN (P= 0.02). Peritubular capillary basement membrane (BM) multilayering was significantly greater in TGP (4.92 +/- 2.94) than in recurrent IgAN (1.86 +/- 1.04) (P < 0.001). The graft survival of TGP was worse than recurrent IgAN (P= 0.05). The association of TGP with BM multilayering and C4d deposits in PTC suggests a generalized disorder of the graft microcirculation and its BM, owing to antibody-mediated rejection in at least some cases. Transplant glomerulopathy has a serious prognosis but is less frequent in patients on newer immunosuppression, unlike recurrent IgAN.
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http://dx.doi.org/10.1046/j.1600-6143.2003.00294.xDOI Listing
January 2004