Publications by authors named "Nicolas Kozakowski"

36 Publications

A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection.

J Am Soc Nephrol 2021 Mar 18;32(3):708-722. Epub 2020 Dec 18.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria

Background: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.

Methods: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.

Results: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m per month, respectively, =0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.

Conclusions: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.
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http://dx.doi.org/10.1681/ASN.2020071106DOI Listing
March 2021

Glomerular C4d in Post-Transplant IgA Nephropathy is associated with decreased allograft survival.

J Nephrol 2020 Dec 11. Epub 2020 Dec 11.

Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Glomerulonephritis (GN), including post-transplant IgAN (post-Tx IgAN) is an important contributor to decreased long-term allograft survival. The immunopathological detection of the complement degradation product C4d in glomeruli (C4dG) has been recently described as a risk factor in native kidney IgAN, however little is known about C4dG deposition in post-Tx IgAN. We hypothesized that glomerular C4d may indicate a more aggressive disease course and worse allograft survival in patients with post-Tx IgAN.

Methods: In this retrospective study we assessed the presence and clinical relevance of C4dG in patients with post-transplant IgAN. We analyzed 885 renal allograft recipients, including 84 patients with post-transplant GN. All patients were transplanted between January 1999 and April 2006 and underwent at least one biopsy for differnt causes. The primary endpoint was death-censored graft survival, with a median follow-up of 9.6 (IQR 3.8-13.2) years.

Results: The prevalence of post-Tx GN was 9.5%. Twenty-seven patients with post-Tx IgAN were included. C4dG positive patients (N = 18, 66.7%) had significantly worse allograft survival compared to C4dG negative post-Tx IgAN patients and patients without post-Tx IgAN [C4dG positive: 27.8% vs. 55.6% and 66.0%; log-rank: p = 0.01]. C4dG remained a significant risk factor (HR 2.22, 95% CI 1.27-3.87) for allograft loss even after adjustment for T cell mediated rejection (TCMR) and antibody mediated rejection.

Conclusion: Glomerular C4d deposition is an independent risk factor for worse graft-survival in patients with post-Tx IgAN, even after adjusting for other risk factors such as antibody mediated rejection.  Assessment of glomerular C4d deposition may provide a valuable prognostic risk assessment tool to identify high risk patients in post-Tx IgAN.
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http://dx.doi.org/10.1007/s40620-020-00914-xDOI 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

Factors influencing agreement of breast cancer luminal molecular subtype by Ki67 labeling index between core needle biopsy and surgical resection specimens.

Virchows Arch 2020 Oct 7;477(4):545-555. Epub 2020 May 7.

Department of Pathology and Comprehensive Cancer Center, Medical University of Vienna, 18-20 Waehringer Guertel, A-1090, Vienna, Austria.

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement. Molecular subtype was determined visually by Ki67-LI in 484 pairs of CNB and SR specimens of invasive estrogen receptor (ER)-positive, human epidermal growth factor (HER2)-negative breast cancer. Luminal B disease was defined by Ki67-LI > 20% in SR. Correlation of molecular subtype agreement with age, menopausal status, CNB method, Breast Imaging Reporting and Data System imaging category, time between biopsies, type of surgery, and pathological tumor parameters was analyzed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. CNB had a sensitivity of 77.95% and a specificity of 80.97% for identifying luminal B tumors in CNB, compared with the final molecular subtype determination after surgery. The correlation of Ki67-LI between CNB and SR was moderate (ROC-AUC 0.8333). Specificity and sensitivity for CNB to correctly define molecular subtype of tumors according to SR were significantly associated with tumor grade, immunohistochemical progesterone receptor (PR) and p53 expression (p < 0.05). Agreement of molecular subtype did not significantly impact RFS and OS (p = 0.22 for both). The identified factors likely mirror intratumoral heterogeneity that might compromise obtaining a representative CNB. Our results challenge the robustness of a single CNB-driven measurement of Ki67-LI to identify luminal B breast cancer of low (G1) or intermediate (G2) grade.
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http://dx.doi.org/10.1007/s00428-020-02818-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508960PMC
October 2020

Non-invasive Chemokine Detection: Improved Prediction of Antibody-Mediated Rejection in Donor-Specific Antibody-Positive Renal Allograft Recipients.

Front Med (Lausanne) 2020 9;7:114. Epub 2020 Apr 9.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Screening for donor-specific antibodies (DSA) has limited diagnostic value in patients with late antibody-mediated rejection (ABMR). Here, we evaluated whether biomarkers reflecting microcirculation inflammation or tissue injury-as an adjunct to DSA detection-are able to improve non-invasive ABMR monitoring. Upon prospective cross-sectional antibody screening of 741 long-term kidney transplant recipients with a silent clinical course, 86 DSA-positive patients were identified and biopsied. Serum and urine levels of E-selectin/CD62E, vascular cell adhesion molecule 1 (VCAM-1), granzyme B, hepatocyte growth factor (HGF), C-C motif chemokine ligand (CCL)3, CCL4, C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL11 in DSA-positive recipients were investigated applying multiplexed bead-based immunoassays. Diagnosis of ABMR (50 patients) was associated with significantly higher levels of CXCL9 and CXCL10 in blood and urine and of HGF in blood. Overall, urinary CXCL9 had the highest diagnostic accuracy for ABMR (area under the receiver operating characteristic curve: 0.77; accuracy: 80%) and its combined evaluation with the mean fluorescence intensity of the immunodominant DSA (DSAmax MFI) revealed a net reclassification improvement of 73% compared to DSAmax MFI alone. Our results suggest urinary CXCL9 testing, combined with DSA analysis, as a valuable non-invasive tool to uncover clinically silent ABMR late after transplantation.
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http://dx.doi.org/10.3389/fmed.2020.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160229PMC
April 2020

High-activity Classical and Alternative Complement Pathway Genotypes-Association With Donor-specific Antibody-triggered Injury and Renal Allograft Survival.

Transplant Direct 2020 Mar 10;6(3):e534. Epub 2020 Feb 10.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Complement may contribute to donor-specific antibody (DSA)-triggered transplant injury. Here, we investigated whether the intrinsic strength of classical pathway and alternative pathway (AP) relates to the pathogenicity of DSA.

Methods: Classical pathway and AP high-activity genotypes were defined according to C4 gene copy number and the presence of functional polymorphisms in C3 (C3), factor B (fB), and factor H (fH) genes. Associations of these genotypes with blood complement profiles and morphologic/molecular rejection features were evaluated in a cohort of 83 DSA-positive patients (antibody-mediated rejection [AMR], n = 47) identified upon cross-sectional screening of 741 kidney allograft recipients ≥180 days posttransplantation. Associations with long-term graft survival were evaluated in a larger kidney transplant cohort (n = 660) not enriched for a specific type of rejection.

Results: In the cohort of DSA-positive subjects, the number of C4 gene copies was related to C4 protein levels in serum and capillary C4d staining, but not AMR activity. Patients with a high-activity AP complotype, which was associated with complement consumption in serum, showed enhanced microcirculation inflammation (median glomerulitis plus peritubular capillaritis score, 2 [interquartile range, 0-4 versus 1 0-2]; = 0.037). In the larger transplant cohort, this complotype was associated with a slightly increased risk of graft loss (hazard ratio, 1.52; 95% confidence interval, 1.02-2.25; = 0.038 and multivariable Cox model, 1.55; 1.04-2.32; = 0.031).

Conclusions: Our study suggests a contribution of complement genetics to the phenotypic presentation of AMR. Future studies will have to clarify whether a possible association of AP strength with graft survival relates to enhanced antibody-triggered injury.
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http://dx.doi.org/10.1097/TXD.0000000000000978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056277PMC
March 2020

Quantitative PCR of INDELs to measure donor-derived cell-free DNA-a potential method to detect acute rejection in kidney transplantation: a pilot study.

Transpl Int 2020 Mar 13;33(3):298-309. Epub 2019 Dec 13.

Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Wien, Austria.

The quantification of donor-derived cell-free DNA (ddcfDNA) in recipient's plasma is a novel, but technically challenging noninvasive method to assist the diagnosis of acute rejection (AR). A quantitative real-time PCR (qPCR) approach targeting insertion/deletion polymorphisms (INDEL) was adapted to measure ddcfNA in plasma samples from 29 kidney transplant recipients obtained at time of clinically indicated biopsies (eight patients with a histologically verified AR, nine with borderline rejection and 12 without evidence of rejection). Measured ddcfDNA levels of smaller INDEL amplicon targets differed significantly (P = 0.016, Kruskal-Wallis H test) between recipients with biopsy-proven AR (median 5.24%; range 1.00-9.03), patients without (1.50%; 0.41-6.50) and patients with borderline AR (1.91%; 0.58-5.38). Similarly, pairwise testing by Mann-Whitney U-tests revealed significant differences between recipients with AR and without AR (P = 0.012) as well as patients with AR and borderline histology (P = 0.015). Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve for discriminating AR and non-AR biopsies of 0.84 (95% CI: 0.66-1.00). The determined cutoff value of 2.7% ddcfDNA showed a sensitivity of 0.88 (95% CI: 0.63-1.00) and specificity of 0.81 (95% CI: 0.64-0.98). INDEL qPCR represents a novel method to quantify ddcfDNA on standard qPCR instruments within 6-8 h with high sensitivity and specificity to detect AR.
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http://dx.doi.org/10.1111/tri.13554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065216PMC
March 2020

Non-invasive screening for sub-clinical antibody-mediated rejection as a new tool for indication of kidney allograft biopsy.

EBioMedicine 2019 Aug 25;46:13-14. Epub 2019 Jul 25.

Department of Pathology, Medical University of Vienna, Vienna, Austria; Sorbonne Université, Université Pierre et Marie Curie Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1155, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710980PMC
August 2019

Complement Markers in Blood and Urine: No Diagnostic Value in Late Silent Antibody-Mediated Rejection.

Transplant Direct 2019 Jul 27;5(7):e470. Epub 2019 Jun 27.

IIIrd Department of Internal Medicine and MTA-SE Research Group of Immunology and Hematology, Research Laboratory, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.

Background: Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure. Its molecular mechanisms are multifaceted and may include a role of complement activation via the classical pathway. Here, we investigated whether noninvasive complement monitoring adds predictive power to the diagnosis of AMR in the setting of donor-specific antibody (DSA) positivity.

Methods: In this cross-sectional study, 741 kidney transplant recipients with stable graft function ≥180 days posttransplantation were screened for the presence of human leukocyte antigen (HLA) alloantibodies. Eighty-three of 111 DSA-positive recipients underwent protocol biopsies and were tested for blood and urinary levels of complement proteins (C1q, C4, C3) and activation products (C4d, C3a, C5a, C5b-9).

Results: Forty-seven recipients were diagnosed with AMR, and 21 were C4d-positive. While biopsy-confirmed AMR (and C4d) associated with DSA-binding strength (IgG mean fluorescence intensity of the immunodominant DSA versus AMR; area under the receiver operating characteristic curve: 0.76), tested complement markers did not have any predictive value for rejection (area under the receiver operating characteristic curve: 0.49-0.56). There were, however, tight correlations between complement activation products in urine and protein/creatinine ratio ( = 0.44-0.64; < 0.001). Analysis of death-censored graft survival over a median of 60 months revealed no independent associations with levels of complement markers in blood or urine.

Conclusions: Complement patterns in blood and urine failed to identify AMR in late biopsies and may have no relevant diagnostic value in this particular context.
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http://dx.doi.org/10.1097/TXD.0000000000000915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616143PMC
July 2019

An integrative approach for the assessment of peritubular capillaritis extent and score in low-grade microvascular inflammation-associations with transplant glomerulopathy and graft loss.

Nephrol Dial Transplant 2019 01;34(1):166-174

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Peritubular capillaritis (ptc), reported by the ptc score, is a major feature of kidney allograft rejection and microvascular inflammation (MVI). MVI sum scores (ptc + glomerulitis score ≥2) are accepted diagnostic surrogates of human leucocyte antigen (HLA)-antibody interaction. However, low-grade inflammation is common and ptc scores (number of leucocytes/capillary) may not mirror all aspects of ptc morphology. Recently we observed a relationship of the diffuse extent of ptc (inflammation of >50% of the renal cortex) with graft loss and significantly higher donor-specific antibody levels, suggesting potential inclusion of diffuse ptc as an additional surrogate of antibody-antigen interaction.

Methods: We sought to assess how a combination of ptc score and extent in low-grade inflammation (ptc1) affects transplant glomerulopathy (TG) and graft loss risk. Patients (n = 616) were assessed for MVI in first indication biopsies. Cases with a ptc score of 1 but diffuse extent (ptc1diffuse, g-score = 0, n = 26) were considered additional surrogates of HLA-antibody interaction and compared with MVI ≥2 and MVI <2.

Results: The ptc1diffuse and MVI score ≥2 subjects had worse graft survival (42% and 59%) compared with an MVI score <2 (70%) (P = 0.002). The incorporation of ptc1diffuse in the MVI score ≥2 increased the receiver operating characteristics curve for TG [area under the curve (AUC) 0.602; P = 0.008] compared with a Banff MVI score ≥2 (AUC 0.56; P = 0.12); cases with baseline TG were excluded. In multivariate analysis, ptc1diffuse remained independently related to TG (odds ratio 3.89; P = 0.008) and graft loss (hazard ratio 2.64; P = 0.001) even after inclusion of all rejection episodes.

Conclusion: An integrated view of ptc morphology including diffuse ptc in MVI is superior for TG and graft loss risk assessment.
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http://dx.doi.org/10.1093/ndt/gfy192DOI Listing
January 2019

Lymphotoxin expression in human and murine renal allografts.

PLoS One 2018 4;13(1):e0189396. Epub 2018 Jan 4.

Division of Nephrology, University Hospital, Zuerich, Switzerland.

The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTβ, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFκB pathway, most likely a consequence of LTβ receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTα, LTβ and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTβ in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754061PMC
January 2018

A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection.

J Am Soc Nephrol 2018 02 14;29(2):591-605. Epub 2017 Dec 14.

Division of Nephrology and Dialysis, Department of Medicine III,

Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (=21) or placebo (=23). The 0.5-ml/min per 1.73 m per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m; =0.31), 2-year graft survival (81% versus 96%; =0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.
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http://dx.doi.org/10.1681/ASN.2017070818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791086PMC
February 2018

MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus.

PLoS One 2017 18;12(7):e0181015. Epub 2017 Jul 18.

Department of Rheumatology, Medical University of Vienna, Vienna, Austria.

Objective: We herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus.

Materials And Methods: Systemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes.

Results: After induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15).

Conclusions: MiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515414PMC
September 2017

NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis.

Clin Chem Lab Med 2017 Nov;56(1):147-156

.

Background: Neutrophil gelatinase associated lipocalin (NGAL) is expressed in atherosclerotic lesions and was recently implicated in the pathogenesis of cardiovascular pathologies. Statins are known to exert stabilizing effects on atherosclerotic plaque. The aims of our study were (1) to investigate the association of serum NGAL and metalloproteinase (MMP)-9/NGAL complex with the vulnerability of the atherosclerotic plaque, and (2) to reveal the effects of statin treatment on circulating NGAL and MMP-9/NGAL levels in patients with carotid artery stenosis.

Methods: We examined the levels of NGAL and MMP-9/NGAL in blood samples from 136 patients with carotid artery stenosis by specific enzyme-linked immunosorbent assays.

Results: Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of American Heart Association [AHA]), displayed the highest levels of NGAL (both p<0.0001) and MMP-9/NGAL complex (p=0.0004 and p=0.004, respectively). Moreover, patients with symptomatic carotid atherosclerosis had significantly higher NGAL levels compared to asymptomatic patients (p=0.0007). The statin-treated group (n=108) demonstrated lower NGAL (73.9 vs. 128.0 μg/L, p<0.0001) and MMP-9/NGAL (28.9 vs. 40.6 μg/L, p=0.046) as compared to the non-statin group (n=28). Furthermore, in multivariate regression analysis NGAL, but not MMP-9/NGAL levels, were independently associated with symptomatic carotid artery stenosis. In addition, statin treatment was independently associated with lower NGAL levels.

Conclusions: Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels.
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http://dx.doi.org/10.1515/cclm-2017-0156DOI Listing
November 2017

The Case | Myeloid bodies in the kidney biopsy of a patient with systemic lupus erythematosus.

Kidney Int 2017 07;92(1):271-272

Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2016.12.025DOI Listing
July 2017

Diffuse Extent of Peritubular Capillaritis in Late Antibody-Mediated Rejection: Associations With Levels of Donor-Specific Antibodies and Chronic Allograft Injury.

Transplantation 2017 05;101(5):e178-e187

1 Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria. 2 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria. 3 Department of Emergency Medicine, Medical University Vienna, Vienna, Austria.

Background: Recently, diffuse peritubular capillaritis (ptc) has been suggested to independently predict chronic transplant injury and loss, and although the ptc score is a diagnostic criterion for antibody-mediated rejection, the utility of diffuse ptc is under debate.

Methods: We evaluated the diagnostic value of ptc characteristics in this cross-sectional study including 85 biopsies of patients with donor-specific antibodies (DSA). Biopsies were reevaluated for the extent (diffuse vs focal), score and leukocytic composition in relation to DSA binding strength (mean fluorescence intensity [MFI]_max). Chronic allograft injury (transplant chronic glomerulopathy [cg] or chronic lesion score CLS]) were associated with ptc features.

Results: Peritubular capillaritis was detected in 50% (76% mononuclear ptc). Peritubular capillaritis scores 1, 2, and 3 were present in 36%, 55%, and 9%, and focal or diffuse ptc in 36% or 64%. Diffuse ptc was associated with DSA MFI_max (median: 4407 vs 2419 [focal ptc; P = 0.04] or 1946 [no ptc; P = 0.004]), cg (58% vs no ptc 24% [P = 0.02]), and higher CLS (mean: 6.81 vs 4.67 [focal ptc, P = 0.01] or 5.18 [no ptc, P = 0.001]), respectively. The association of ptc score of 2 or greater with cg was slightly better than with diffuse ptc. Diffuse ptc and ptc score of 2 or greater remained independently related to cg after adjusting for DSA_MFI_max, C4d, or previous rejection episodes, however lost their independent relation after adjusting for total microcirculation scores. Diffuse ptc was the only ptc characteristic independently related to CLS.

Conclusions: Our results emphasize the clinical relevance of reporting diffuse ptc, which may relate to DSA binding strength and potentially to chronic graft injury.
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http://dx.doi.org/10.1097/TP.0000000000001707DOI Listing
May 2017

Torque Teno Virus Load-Inverse Association With Antibody-Mediated Rejection After Kidney Transplantation.

Transplantation 2017 02;101(2):360-367

1 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Austria. 2 Department of Virology, Medical University of Vienna, Austria. 3 Division of Transplant Surgery, Department of Surgery, Medical University of Vienna, Austria. 4 Division of Nephrology and Gastroenterology, Department of Pediatrics, Medical University of Vienna, Austria. 5 Department of Clinical Pathology, Medical University of Vienna, Austria. 6 Department of Emergency Medicine, Medical University of Vienna, Austria.

Background: Antibody-mediated rejection (AMR) represents one of the cardinal causes of late allograft loss after kidney transplantation, and there is great need for noninvasive tools improving early diagnosis of this rejection type. One promising strategy might be the quantification of peripheral blood DNA levels of the highly prevalent and apathogenic Torque Teno virus (TTV), which might mirror the overall level of immunosuppression and thus help determine the risk of alloimmune response.

Methods: To assess the association between TTV load in the peripheral blood and AMR, 715 kidney transplant recipients (median, 6.3 years posttransplantation) were subjected to a systematical cross-sectional AMR screening and, in parallel, TTV quantification.

Results: Eighty-six of these recipients had donor-specific antibodies and underwent protocol biopsy, AMR-positive patients (n = 46) showed only 25% of the TTV levels measured in patients without AMR (P = 0.003). In a generalized linear model, higher TTV levels were associated with a decreased risk for AMR after adjustment for potential confounders (risk ratio 0.94 per TTV log level; 95% confidence interval 0.90-0.99; P = 0.02).

Conclusions: Future studies will have to clarify whether longitudinal assessment of TTV load might predict AMR risk and help guide the type and intensity of immunosuppression to prevent antibody-mediated graft injury.
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http://dx.doi.org/10.1097/TP.0000000000001455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268087PMC
February 2017

Deceased donor kidney transplantation across donor-specific antibody barriers: predictors of antibody-mediated rejection.

Nephrol Dial Transplant 2016 08 24;31(8):1342-51. Epub 2016 Mar 24.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria.

Background: Apheresis-based desensitization allows for successful transplantation across major immunological barriers. For donor-specific antibody (DSA)- and/or crossmatch-positive transplantation, however, it has been shown that even intense immunomodulation may not completely prevent antibody-mediated rejection (ABMR).

Methods: In this study, we evaluated transplant outcomes in 101 DSA+ deceased donor kidney transplant recipients (transplantation between 2009 and 2013; median follow-up: 24 months) who were subjected to immunoadsorption (IA)-based desensitization. Treatment included a single pre-transplant IA session, followed by anti-lymphocyte antibody and serial post-transplant IA. In 27 cases, a positive complement-dependent cytotoxicity crossmatch (CDCXM) was rendered negative immediately before transplantation. Seventy-four of the DSA+ recipients had a negative CDCXM already before IA.

Results: Three-year death-censored graft survival in DSA+ patients was significantly worse than in 513 DSA- recipients transplanted during the same period (79 versus 88%, P = 0.008). Thirty-three DSA+ recipients (33%) had ABMR. While a positive baseline CDCXM showed only a trend towards higher ABMR rates (41 versus 30% in CDCXM- recipients, P = 0.2), DSA mean fluorescence intensity (MFI) in single bead assays significantly associated with rejection, showing 20 versus 71% ABMR rates at <5000 versus >15 000 peak DSA MFI. The predictive value of MFI was moderate, with the highest accuracy at a median of 13 300 MFI (after cross-validation: 0.72). Other baseline variables, including CDC assay results, human leukocyte antigen mismatch, prior transplantation or type of induction treatment, did not add independent predictive information.

Conclusions: IA-based desensitization failed to prevent ABMR in a considerable number of DSA+ recipients. Assessing DSA MFI may help stratify risk of rejection, supporting its use as a guide to organ allocation and individualized treatment.
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http://dx.doi.org/10.1093/ndt/gfw027DOI Listing
August 2016

Kidney Transplantation With Corticosteroids Alone After Haploidentical HSCT From The Same Donor.

Transplantation 2016 Oct;100(10):2219-21

1 Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria. 2 Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria. 3 St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria. 4 Department of Internal Medicine III/Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria. 5 Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria. 6 Department of Internal Medicine I, Division of Bone Marrow Transplantation, Medical University of Vienna, Vienna, Austria. 7 Division of Hematology, Medical University of Graz, Graz, Austria. 8 Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to donor-specific tolerance. Patients reported in the literature that underwent kidney transplantation (KT) after a previous HSCT from the same haploidentical donor typically received short-term immunosuppression, mainly for safety reasons and concerns of triggering graft-versus-host disease.

Methods: We describe the case of a 22-year-old patient who developed chronic kidney failure after receiving haploidentical HSCT from his father for the treatment of metastatic rhabdomyosarcoma. Five years after HSCT, he received a preemptive kidney transplant from his father. Steroid treatment, which had been prescribed for the underlying kidney disease, was withdrawn within 2 months posttransplant, and no de novo immunosuppression was given. Donor-specific tolerance was assessed with mixed lymphocyte reaction and INF-γ ELISPOT before (D0) and after KT (D9). Furthermore, the exact level of donor-derived T cells was measured with real-time polymerase chain reaction before and 1 year after KT.

Results: In vitro assays (mixed lymphocyte reaction and ELISPOT) revealed donor-specific tolerance before and after transplantation, respectively. The number of recipient-derived T cells was low before KT and virtually did not change over time (0.0139% ± 0.0039 and 0.0120% ± 0.0067; P = NS). Graft function was excellent throughout the follow-up (36 months post KT: serum creatinine, 1.18 mg/dL). Protocol biopsies performed 1 and 12 months after transplantation confirmed the absence of rejection.

Conclusions: This is one of the first cases of kidney transplantation from the same donor after previous haploidentical HSCT with a corticosteroid taper alone. Our results suggest that immunosuppression can be avoided in such cases.
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http://dx.doi.org/10.1097/TP.0000000000001213DOI Listing
October 2016

Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated Rejection-Results of a Cross-Sectional Screening Study.

Transplantation 2017 Mar;101(3):631-641

1 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria. 2 Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada. 3 Department of Clinical Pathology, Medical University Vienna, Vienna, Austria. 4 Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria. 5 Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Vienna, Austria. 6 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada. 7 Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Background: Circulating donor-specific antibodies (DSA) detected on bead arrays may not inevitably indicate ongoing antibody-mediated rejection (AMR). Here, we investigated whether detection of complement-fixation, in parallel to IgG mean fluorescence intensity (MFI), allows for improved prediction of AMR.

Methods: Our study included 86 DSA+ kidney transplant recipients subjected to protocol biopsy, who were identified upon cross-sectional antibody screening of 741 recipients with stable graft function at 6 months or longer after transplantation. IgG MFI was analyzed after elimination of prozone effect, and complement-fixation was determined using C1q, C4d, or C3d assays.

Results: Among DSA+ study patients, 44 recipients (51%) had AMR, 24 of them showing C4d-positive rejection. Although DSA number or HLA class specificity were not different, patients with AMR or C4d + AMR showed significantly higher IgG, C1q, and C3d DSA MFI than nonrejecting or C4d-negative patients, respectively. Overall, the predictive value of DSA characteristics was moderate, whereby the highest accuracy was computed for peak IgG MFI (AMR, 0.73; C4d + AMR, 0.71). Combined analysis of antibody characteristics in multivariate models did not improve AMR prediction.

Conclusions: We estimate a 50% prevalence of silent AMR in DSA+ long-term recipients and conclude that assessment of IgG MFI may add predictive accuracy, without an independent diagnostic advantage of detecting complement-fixation.
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http://dx.doi.org/10.1097/TP.0000000000001195DOI Listing
March 2017

The Phenotypic Characterization of the Human Renal Mononuclear Phagocytes Reveal a Co-Ordinated Response to Injury.

PLoS One 2016 21;11(3):e0151674. Epub 2016 Mar 21.

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.

Mammalian tissues contain networks of mononuclear phagocytes (MPh) that sense injury and orchestrate the response to it. In mice, this is affected by distinct populations of dendritic cells (DC), monocytes and macrophages and recent studies suggest the same is true for human skin and intestine but little is known about the kidney. Here we describe the analysis of MPh populations in five human kidneys and show they are highly heterogeneous and contain discrete populations of DC, monocytes and macrophages. These include: plasmacytoid DC (CD303+) and both types of conventional DC-cDC1 (CD141+ cells) and CD2 (CD1c+ cells); classical, non-classical and intermediate monocytes; and macrophages including a novel population of CD141+ macrophages clearly distinguishable from cDC1 cells. The relative size of the MPh populations differed between kidneys: the pDC population was bi-modally distributed being less than 2% of DC in two kidneys without severe injury and over 35% in the remaining three with low grade injury in the absence of morphological evidence of inflammation. There were profound differences in the other MPh populations in kidneys with high and low numbers of pDC. Thus, cDC1 cells were abundant (55 and 52.3%) when pDC were sparse and sparse (12.8-12.5%) when pDC were abundant, whereas the proportions of cDC2 cells and classical monocytes increased slightly in pDC high kidneys. We conclude that MPh are highly heterogeneous in human kidneys and that pDC infiltration indicative of low-grade injury does not occur in isolation but is part of a co-ordinated response affecting all renal DC, monocyte and macrophage populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151674PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801374PMC
August 2016

The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.

Kidney Int 2016 Jan 4;89(1):113-26. Epub 2016 Jan 4.

Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. Electronic address:

Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
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http://dx.doi.org/10.1038/ki.2015.280DOI Listing
January 2016

Capillary C4d and Kidney Allograft Outcome in Relation to Morphologic Lesions Suggestive of Antibody-Mediated Rejection.

Clin J Am Soc Nephrol 2015 Aug 12;10(8):1435-43. Epub 2015 Jun 12.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria;

Background And Objectives: Recent studies highlighting a role of C4d- antibody-mediated rejection (ABMR) have debated whether C4d staining has independent value as a rejection marker. Considering the presumed role of complement as an important effector of graft injury, this study hypothesized that capillary C4d, a footprint of antibody-triggered complement activation, indicates a particularly severe manifestation of ABMR.

Design, Setting, Participants, & Measurements: This large retrospective clinicopathologic study sought to assess the clinical predictive value of C4d staining in relation to ABMR morphology. Overall, 885 renal allograft recipients who underwent transplantation between 1999 and 2006 (median duration of follow-up, 63.3 [interquartile range, 40.6-93.5] months; 206 graft losses) were included if they had had one or more indication biopsies. A total of 1976 biopsy specimens were reevaluated for capillary C4d staining (C4d data were available for 825 patients) and distinct morphologic lesions suggestive of ABMR, including glomerulitis, peritubular capillaritis, capillary microthrombi, transplant glomerulopathy, and severe intimal arteritis.

Results: C4d+ patients, with or without ABMR features, had worse death-censored 8-year graft survival (53% or 67%) than C4d- patients (66% or 81%; P<0.001). In Cox regression analysis, C4d was associated with a risk of graft loss independently of baseline confounders and ABMR morphology (hazard ratio, 1.85 [95% confidence interval, 1.34 to 2.57]; P<0.001). The risk was higher than that observed for C4d- patients, a finding that reached statistical significance in patients showing fewer than two different ABMR lesions. Moreover, in a mixed model, C4d was independently associated with a steeper decline of eGFR (slope per year, -8.23±3.97 ml/min per 1.73 m(2); P<0.001).

Conclusions: These results suggest that detection of intragraft complement activation has strong independent value as an additional indicator of ABMR associated with adverse kidney transplant outcomes.
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http://dx.doi.org/10.2215/CJN.09901014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527028PMC
August 2015

The diffuse extent of peritubular capillaritis in renal allograft rejection is an independent risk factor for graft loss.

Kidney Int 2015 Aug 4;88(2):332-40. Epub 2015 Mar 4.

Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.

By the Banff classification, the score of peritubular capillaritis, its extent, and its cellular composition should normally be reported in renal allograft pathology. While the score represents an important diagnostic and prognostic variable, the clinical value of capillaritis extent or composition has yet to be resolved. In a retrospective study of 749 renal transplant recipients subjected to 1322 indication biopsies, we found that prevalence scores of 1, 2, or 3 in the biopsy specimens were 10.7, 11.6, and 2.6%, respectively. Focal and diffuse peritubular capillaritis (inflammation over 50% of cortical peritubular capillaries) was diagnosed in 10.5 or 14.4% of cases, respectively. Mononuclear, granulocytic, and mixed peritubular capillaritis was present in 13.1, 3.3, and 8.5%, respectively. While peritubular capillaritis without further subclassification was not related to higher allograft loss rates, a score of 3 (hazard ratio 2.57 (CI: 1.25-5.28)) and diffuse peritubular capillaritis (1.67 (1.1-2.54)) were significant impartial risk factors for allograft loss. Diffuse peritubular capillaritis was independently associated with features of chronic antibody-mediated rejection and greater eGFR decline after 3 years. In contrast, detailed report of leukocytic composition in peritubular capillaritis did not confer additional prognostic information. Thus, in contrast to typing the infiltrating inflammatory cells, the score and extent of peritubular capillaritis in kidney allograft pathology is essential to assess transplant prognosis.
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http://dx.doi.org/10.1038/ki.2015.64DOI Listing
August 2015

Efficacy of fosfomycin compared to vancomycin in treatment of implant-associated chronic methicillin-resistant Staphylococcus aureus osteomyelitis in rats.

Antimicrob Agents Chemother 2014 Sep 16;58(9):5111-6. Epub 2014 Jun 16.

Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria

Fosfomycin monotherapy was compared to therapy with vancomycin for the treatment of implant-associated methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in an experimental rat model. The proximal tibiae were inoculated with 15 μl of a suspension containing 1×10(8) to 5×10(8) CFU/ml of a clinical isolate of MRSA with simultaneous insertion of a titanium wire. Four weeks later, treatment was started for 28 days with either 50 mg/kg of body weight vancomycin intraperitoneally twice daily (n=11) or 75 mg/kg fosfomycin intraperitoneally once daily (n=10). Eleven animals were left untreated. After treatment, quantitative cultures from bone were found to be positive for MRSA in all animals in the untreated group (median, 3.29×10(6) CFU/g of bone) and the vancomycin group (median, 3.03×10(5) CFU/g of bone). In the fosfomycin group, MRSA was detectable in 2 out of 10 (20%) animals (3.42×10(2) and 1.51×10(3) CFU/g of bone). Vancomycin was superior to the no-drug control (P=0.002), and fosfomycin was superior to the no-drug control and vancomycin (P<0.001). The cultures from the wires were positive in all untreated animals (median, 2.5×10(3) CFU/implant), in 10 animals in the vancomycin group (median, 1.15×10(3) CFU/implant), and negative in all animals in the fosfomycin group. Based on the bacterial counts from the implants, vancomycin was not superior to the no-drug control (P=0.324), and fosfomycin was superior to the no-drug control and vancomycin (P<0.001). No emergence of resistance was observed. In conclusion, it was demonstrated that fosfomycin monotherapy is highly effective for the treatment of experimental implant-associated MRSA osteomyelitis.
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http://dx.doi.org/10.1128/AAC.02720-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135863PMC
September 2014

Late Antibody-Mediated Rejection in a Large Prospective Cross-Sectional Study of Kidney Allograft Recipients--Preliminary Results of the Screening Phase of the BORTEJECT Trial.

Clin Transpl 2014 :189-95

There is limited data on the rate of late antibody-mediated rejection (ABMR) in unselected transplant cohorts. Here, we investigated the prevalence and characteristics of ABMR in a large cohort of long-term kidney allograft recipients. Patients were screened in the context of a randomized controlled trial (BORTEJECT study; ClinicalTrials.gov: NCT01873157) designed to investigate the impact of bortezomib on the course of late ABMR. The study (initiation in October 2013) includes a cross-sectional ABMR screening (key inclusion criterion: functioning graft at ≥ 180 days) to identify 44 recipients eligible for inclusion in the intervention trial. Patients were screened for donor-specific antibodies (DSA) applying solid phase technology and DSA+ recipients underwent protocol biopsies. Through November 2014, ABMR screening (after a median of 6.5 years post-transplantation) had been completed for 714 recipients. One hundred one patients (14%) had DSA above a threshold of 1,000 mean fluorescence intensity (MFI). Forty-four of 78 DSA+ recipients (6% of the overall cohort) subjected to biopsy were diagnosed with C4d-positive (n = 17) or -negative (n = 27) ABMR and 40 consented to participate in the intervention trial. DSA+ABMR+ and DSA+ABMR- patients differed significantly with respect to the MFI of the highest level DSA (P < 0.001), whereby ABMR or C4d positivity were moderately predicted by MFI values (area under the receiver operating characteristic curve: 0.75 and 0.84, respectively). In conclusion, the results of this cross-sectional analysis suggest a ≥ 6% prevalence of late ABMR. We demonstrate that the more frequent finding of circulating DSA may not necessarily associate with ABMR diagnosis, especially in patients with low antibody levels.
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September 2015

Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts.

Transpl Int 2014 Mar 16;27(3):312-21. Epub 2014 Jan 16.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria.

While linear C4d staining in peritubular capillaries (PTC) is established as a marker of antibody-mediated rejection, the significance of a distinct granular C4d deposition pattern has not yet been clarified. In this study, 329 renal allograft recipients who underwent indication biopsies were analysed for immunohistochemical C4d staining characteristics. Fifty-six (17%) recipients showed granular C4d in PTC, without any relationship to conventional risk factors and morphological features of rejection. We found a strong association with long-term overall graft survival (7-year survival: 41% vs. 66% in granular C4d-negative subjects, P=0.001), which was mainly driven by a greater risk of mortality [hazard ratio: 3.12 (95% confidence interval: 1.23-7.94); P=0.02]. Granular C4d was associated with delayed graft function [39% vs. 22% (C4d-negative subjects), P=0.007], higher 1-year serum creatinine [median 2.1 (interquartile range: 1.7-2.6) mg/dl vs. 1.6 (1.3-2.0) mg/dl, P=0.001] and a trend towards worse death-censored graft survival (P=0.07). In support of a role of capillary immune complex formation, granular C4d was associated with electron-dense deposits in PTC basement membranes, which were occasionally accompanied by focally distributed capillary IgG deposits. In conclusion, our study suggests clinical relevance of detecting capillary granular C4d deposition. Our results point to a pathogenetic role of alloimmune-independent immune complex deposition.
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http://dx.doi.org/10.1111/tri.12254DOI Listing
March 2014

Immunohistochemical expression of PDGFR, VEGF-C, and proteins of the mToR pathway before and after androgen deprivation therapy in prostate carcinoma: significant decrease after treatment.

Target Oncol 2014 Dec 17;9(4):359-66. Epub 2013 Nov 17.

Clinical Institute for Pathology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Targeted therapy in hormone refractory prostate cancer (HRPC) is currently under evaluation in many trials. The effect of androgen deprivation therapy (ADT) on many targets in prostate cancer is incompletely known. For the first time, immunohistochemical expression of the platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor C (VEGF-C), mammalian target of rapamycin (mToR), p70 ribosomal protein S6 kinase 1 (PS6K), human epidermal growth factor receptor 2 (c-erbB-2), and carbonic anhydrase IX (CA9) was evaluated in 44 patients with prostate carcinoma treated with or without ADT, at biopsy time and after radical prostatectomy. PDGFR, VEGF-C, mToR, and PS6K expression was significantly reduced (p = 0.002, p = 0.035, p = 0.025, and p = 0.033, respectively) after ADT, whereas expression of EGFR, c-erbB-2, and CA9 was not influenced by ADT. In conclusion, targeting PDGFR, VEGF-C, mToR, or PS6K after ADT should be considered with precaution, as those targets can severely be altered or functionally deregulated by ADT.
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http://dx.doi.org/10.1007/s11523-013-0298-1DOI Listing
December 2014

Pretransplant risk stratification for early survival of renal allograft recipients.

Eur J Clin Invest 2014 Feb 9;44(2):168-75. Epub 2013 Dec 9.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Baseline comorbidities influence patient outcomes in renal transplantation. Identification of high-risk recipients for patient death and early allograft loss might lead to superior stratification.

Material And Methods: In this retrospective study, risk stratification models were developed in a cohort of 392 kidney transplant recipients and validated in an independent cohort to predict short-term (2 year) outcomes.

Results: Peripheral arterial disease [OR 7·7 (95% confidence interval (CI): 2·45-24·60); P < 0·001], use of oral anticoagulation [OR 18·68 (95% CI: 3·77-92·46); P < 0·0001], smoking [OR 5·15 (95% CI: 1·67-15·84); P = 0·004], recipient age > 60 years [OR 7·28 (95% CI: 2·33-22·69; P = 0·001)], serum albumin < 40 g/L [OR 5·08 (95% CI: 1·82-14·19); P = 0·002], serum calcium ≥ 2·42 mM [OR 6·47 (95% CI: 1·37-30·58); P = 0·02] living donation [OR 2·95, (95% CI: 0·31-28·29); P = 0·34)] and previous haemodialysis [OR 3·33, (95% CI: 0·39-28·11); P = 0·27)] were included in the model. The validated model discriminated between low- (< 3 points) and high-risk recipients (> 8·5 points) with mortality rates of 0% vs. 54%. The comparison of the model with the Charlson comorbidity index (CCI) yielded significantly better receiver operating characteristic (ROC) areas (Novel Score ROC: 0·87 vs. CCI: 0·72, P = 0·0012). Early allograft loss was associated with presensitization [OR 3·02 (95% CI: 1·29-7·09); P = 0·011] and presence of hepatitis C antibodies [OR 2·42 (95% CI: 1·09-5·34); P = 0·029]. A risk model (ROC: 0·62) for allograft loss could not be developed.

Conclusion: Risk stratification based on the novel score might identify high-risk recipients with disproportional risk of early patient death and lead to optimized strategies.
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http://dx.doi.org/10.1111/eci.12203DOI Listing
February 2014

Renal elimination of sclerostin increases with declining kidney function.

J Clin Endocrinol Metab 2014 Jan 20;99(1):248-55. Epub 2013 Dec 20.

Department of Medicine III (D.C., M.P., T.R., M.H.), Division of Nephrology and Dialysis, Department of Laboratory Medicine (R.M.), Clinical Institute of Pathology (N.K.), and Department of Medicine III (A.G.), Division of Endocrinology and Metabolism, Medical University Vienna (D.C., R.M., N.K., M.P., T.R., A.G., M.H.), 1090 Vienna, Austria.

Context: Sclerostin serum levels are increased in patients with chronic kidney disease (CKD). Osteoporosis and CKD often occur simultaneously. Currently antisclerostin antibodies are in clinical development for the treatment of osteoporosis.

Objective: The objective of this study was to study the renal handling of sclerostin.

Design: This was a cross-sectional study.

Setting: The study was conducted at a university hospital and outpatient renal clinic.

Patients: One hundred twenty men and women with CKD stage 1-5 participated in the study.

Intervention: Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, α1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry.

Main Outcome Measure: Urinary excretion of sclerostin was measured.

Results: Urinary sclerostin excretion increased with declining eGFR (R=-0.75, P<.001), from 10.4 (±12.7) pmol/L in patients with eGFR greater than 90 mL/min per 1.73 m2 (CKD stage 1) to 117.9 (±65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m2 (CKD stage 5, P<.001). Fractional excretion of sclerostin increased with declining eGFR (R=-0.83, P<.001) from 0.45% (±0.6%) in CKD 1 to 26.3% (±17.6%) in CKD 5 (P<.001). Fractional excretion of sclerostin correlated with fractional excretion of α1-microglobulin (R=0.82, P<.001). No association between serum sclerostin and fractional excretion of phosphorus was found in a multivariate analysis. Sclerostin was detected in proximal tubular cells, showing a diffuse cytoplasmic staining pattern.

Conclusion: Increased sclerostin serum levels in CKD patients are not due to decreased renal elimination. On the contrary, renal elimination increases with declining kidney function. Whether this has consequences on antisclerostin antibody dosing, efficacy, or safety in patients with CKD remains to be determined.
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http://dx.doi.org/10.1210/jc.2013-2786DOI Listing
January 2014