Publications by authors named "Mira Choi"

78 Publications

Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis.

Front Immunol 2021 30;12:690698. Epub 2021 Jun 30.

Department of Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Patients with kidney failure have notoriously weak responses to common vaccines. Thus, immunogenicity of novel SARS-CoV-2 vaccines might be impaired in this group. To determine immunogenicity of SARS-CoV-2 vaccination in patients with chronic dialysis, we analyzed the humoral and T-cell response after two doses of mRNA vaccine Tozinameran (BNT162b2 BioNTech/Pfizer). This observational study included 43 patients on dialysis before vaccination with two doses of Tozinameran 21 days apart. Overall, 36 patients completed the observation period until three weeks after the second dose and 32 patients were further analyzed at week 10. Serum samples were analyzed by SARS-CoV-2 specific IgG and IgA antibodies ~1, ~3-4 and ~10 weeks after the second vaccination. In addition, SARS-CoV-2-specific T-cell responses were assessed at ~3-4 weeks by an interferon-gamma release assay (IGRA). Antibody and T cell outcomes at this timepoint were compared to a group of 44 elderly patients not on dialysis, after immunization with Tozinameran. Median age of patients on chronic dialysis was 74.0 years (IQR 66.0, 82.0). The proportion of males was higher (69.4%) than females. Only 20/36 patients (55.6%, 95%CI: 38.29-71.67) developed SARS-CoV-2-IgG antibodies at the first sampling, whereas 32/36 patients (88.9%, 95%CI: 73.00-96.38) demonstrated IgG detection at the second sampling. In a longitudinal follow-up at ~10 weeks after the second dose, the proportion of dialysis patients reactive for anti-SARS-CoV-2-IgG decreased to 27/32 (84.37%, 95%CI: 66.46-94.10) The proportion of anti-SARS-CoV-2 S1 IgA decreased from 33/36 (91.67%; 95%CI: 76.41-97.82) at weeks 3-4 down to 19/32 (59.38; 95%CI: 40.79-75.78). Compared to a cohort of vaccinees with similar age but not on chronic dialysis seroconversion rates and antibody titers were significantly lower. SARS-CoV-2-specific T-cell responses 3 weeks after second vaccination were detected in 21/31 vaccinated dialysis patients (67.7%, 95%CI: 48.53-82.68) compared to 42/44 (93.3%, 95%CI: 76.49-98.84) in controls of similar age. Patients on dialysis demonstrate a delayed, but robust immune response three to four weeks after the second dose, which indicates effective vaccination of this vulnerable group. However, the lower immunogenicity of Tozinameran in these patients needs further attention to develop potential countermeasures such as an additional booster vaccination.
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http://dx.doi.org/10.3389/fimmu.2021.690698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284337PMC
July 2021

Detection of pre-existing SARS-CoV-2-reactive T cells in unexposed renal transplant patients.

J Nephrol 2021 Jul 6. Epub 2021 Jul 6.

Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Hölkeskampring 40, 44625, Herne, Germany.

Background: Recent data demonstrate potentially protective pre-existing T cells reactive against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in samples of healthy blood donors, collected before the SARS-CoV-2 pandemic. Whether pre-existing immunity is also detectable in immunosuppressed patients is currently not known.

Methods: Fifty-seven patients were included in this case-control study. We compared the frequency of SARS-CoV-2-reactive T cells in the samples of 20 renal transplant (RTx) patients to 20 age/gender matched non-immunosuppressed/immune competent healthy individuals collected before the onset of the SARS-CoV-2 pandemic. Seventeen coronavirus disease 2019 (COVID-19) patients were used as positive controls. T cell reactivity against Spike-, Nucleocapsid-, and Membrane- SARS-CoV-2 proteins were analyzed by multi-parameter flow cytometry. Antibodies were analyzed by neutralization assay.

Results: Pre-existing SARS-CoV-2-reactive T cells were detected in the majority of unexposed patients and healthy individuals. In RTx patients, 13/20 showed CD4 T cells reactive against at least one SARS-CoV-2 protein. CD8 T cells reactive against at least one SARS-CoV-2 protein were demonstrated in 12/20 of RTx patients. The frequency and Th1 cytokine expression pattern of pre-formed SARS-CoV-2 reactive T cells did not differ between RTx and non-immunosuppressed healthy individuals.

Conclusions: This study shows that the magnitude and functionality of pre-existing SARS-CoV-2 reactive T cell in transplant patients is non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection.
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http://dx.doi.org/10.1007/s40620-021-01092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259083PMC
July 2021

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients.

Sci Immunol 2021 06;6(60)

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.
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http://dx.doi.org/10.1126/sciimmunol.abj1031DOI Listing
June 2021

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.

J Clin Invest 2021 07;131(14)

Department for General and Visceral Surgery and.

Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.
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http://dx.doi.org/10.1172/JCI150175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279581PMC
July 2021

Undoubtedly, kidney transplant recipients have a higher mortality due to COVID-19 disease compared to the general population.

Transpl Int 2021 05;34(5):769-771

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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http://dx.doi.org/10.1111/tri.13881DOI Listing
May 2021

Dental Caries in Adults with Atopic Dermatitis: A Nationwide Cross-Sectional Study in Korea.

Ann Dermatol 2021 Apr 8;33(2):154-162. Epub 2021 Mar 8.

Department of Dermatology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea.

Background: Dental caries is the most prevalent chronic infectious oral disease of multifactorial etiology. Increased risk of dental caries development in patients with asthma and allergic rhinitis has been frequently reported. In contrast, only a few studies on dental caries in patients with atopic dermatitis (AD) have been reported.

Objective: We investigated the association between AD and dental caries development in an adult population in the Republic of Korea.

Methods: A total of 21,606 adults who participated in the Korean National Health and Nutrition Examination Survey, a nationwide, population-based, cross-sectional survey between 2010 and 2015, were included in the study. Multiple logistic regression analyses with confounder adjustment suggested odds ratios (ORs) to identify the possible association between AD and decayed, missing, filled teeth (DMFT) experience compared to non-AD participants. Multiple Poisson regression analyses estimated the mean ratio of the DMFT index according to the presence of AD.

Results: After adjusting for various confounding factors, the prevalence of DMFT was significantly associated with AD (OR, 1.58; 95% confidence interval (CI), 1.08~2.29; =0.017). In addition, the mean value of the DMFT index was significantly different between the AD and non-AD groups (mean ratio, 1.07; 95% CI, 1.00~1.14; =0.046).

Conclusion: AD was significantly associated with the development of dental caries. Dermatologists should be aware of the dental manifestations of AD patients and recommend regular dental check-ups for the early detection of caries.
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http://dx.doi.org/10.5021/ad.2021.33.2.154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081999PMC
April 2021

Validity of Diagnostic Codes for Identification of Psoriasis Patients in Korea.

Ann Dermatol 2020 Apr 11;32(2):115-121. Epub 2020 Mar 11.

Department of Dermatology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea.

Background: Recently, the number of nationwide medical researches on psoriasis using the National Health Insurance Service database has been on the rise. However, identification of psoriasis using diagnostic codes alone can lead to misclassification. Accuracy of the diagnostic codes and their concordance with medical records should be validated first to identify psoriasis patients correctly.

Objective: To validate the diagnostic codes of psoriasis (International Classification of Diseases, 10th Revision L40) and to find the algorithm for the identification of psoriasis.

Methods: We collected medical records of patients who received their first diagnostic codes of psoriasis during 5 years from five hospitals. Fifteen percent of psoriasis patients were randomly selected from each hospital. We performed a validation by reviewing medical records and compared 5 algorithms to identify the best algorithm.

Results: Total of 538 cases were reviewed and classified as psoriasis (n=368), not psoriasis (n=159), and questionable (n=11). The most accurate algorithm was including patients with ≥1 visits with psoriasis as primary diagnostic codes and prescription of vitamin D derivatives. Its positive predictive value was 96.5% (95% confidence interval [CI], 93.9%~98.1%), which was significantly higher than those of the algorithm, including patients with ≥1 visits with psoriasis as primary diagnostic codes or including ≥1 visits with diagnostic codes of psoriasis (primary or additional) (91.0% and 69.8%). Sensitivity was 90.8% (95% CI, 87.2%~93.4%) and specificity was 92.5% (95% CI, 86.9%~95.9%).

Conclusion: Our study demonstrates a validated algorithm to identify psoriasis, which will be useful for the nationwide population-based study of psoriasis in Korea.
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http://dx.doi.org/10.5021/ad.2020.32.2.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992553PMC
April 2020

Digital Home-Monitoring of Patients after Kidney Transplantation: The MACCS Platform.

J Vis Exp 2021 04 12(170). Epub 2021 Apr 12.

Department of Nephrology and internal intensive Care, Charité Universitätsmedizin Berlin;

The MACCS (Medical Assistant for Chronic Care Service) platform enables secure sharing of key medical information between patients after kidney transplantation and physicians. Patients provide information such as vital signs, well-being, and medication intake via smartphone apps. The information is transferred directly into a database and electronic health record at the kidney transplant center, which is used for routine patient care and research. Physicians can send an updated medication plan and laboratory data directly to the patient app via this secure platform. Other features of the app are medical messages and video consultations. Consequently, the patient is better-informed, and self-management is facilitated. In addition, the transplant center and the patient's local nephrologist automatically exchange notes, medical reports, laboratory values, and medication data via the platform. A telemedicine team reviews all incoming data on a dashboard and takes action, if necessary. Tools to identify patients at risk for complications are under development. The platform exchanges data via a standardized secure interface (Health Level 7 (HL7), Fast Healthcare Interoperability Resources (FHIR)). The standardized data exchange based on HL7 FHIR guarantees interoperability with other eHealth solutions and allows rapid scalability to other chronic diseases. The underlying data protection concept is in concordance with the latest European General Data Protection Regulation. Enrollment started in February 2020, and 131 kidney transplant recipients are actively participating as of July 2020. Two large German health insurance companies are currently funding the telemedicine services of the project. The deployment for other chronic kidney diseases and solid organ transplant recipients is planned. In conclusion, the platform is designed to enable home monitoring and automatic data exchange, empower patients, reduce hospitalizations, and improve adherence, and outcomes after kidney transplantation.
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http://dx.doi.org/10.3791/61899DOI Listing
April 2021

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

Genet Med 2021 Jul 12;23(7):1219-1224. Epub 2021 Mar 12.

Medizinische Genetik Mainz, Limbach Genetics GmbH, Mainz, Germany.

Purpose: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder.

Methods: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders.

Results: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected.

Conclusion: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.
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http://dx.doi.org/10.1038/s41436-021-01127-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257480PMC
July 2021

Targeting Cholesterol Metabolism as Efficient Antiviral Strategy Against the Hepatitis E Virus.

Cell Mol Gastroenterol Hepatol 2021 15;12(1):159-180. Epub 2021 Feb 15.

Department Virology, Paul-Ehrlich-Institut, Langen, Germany. Electronic address:

Background And Aims: The Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals.

Methods: Intracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits.

Results: In HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism.

Conclusions: This study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated.
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http://dx.doi.org/10.1016/j.jcmgh.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099564PMC
February 2021

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo.

J Am Acad Dermatol 2021 Jun 25;84(6):1619-1627. Epub 2021 Jan 25.

Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Electronic address:

Background: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial.

Objective: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy.

Methods: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports.

Results: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer.

Limitations: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races.

Conclusion: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.
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http://dx.doi.org/10.1016/j.jaad.2021.01.067DOI Listing
June 2021

Coronavirus Disease 2019 Associated Risk Score, Behavior, and Symptom Prevalence in German Transplant Recipients.

Transplant Proc 2021 May 16;53(4):1245-1248. Epub 2020 Dec 16.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, BIH Center for Regenerative Therapies, and Institute of Medical Immunology, Berlin, Germany; Ruhr-University Bochum, Marien Hospital Herne, Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Herne, Germany. Electronic address:

Background: Transplant recipients are prone to developing severe infections because of immunosuppression. Therefore, studying the manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients is of particular importance.

Methods: One hundred twelve transplant patients consecutively visiting the outpatient department of 2 German transplant centers were included in this study after providing written informed consent. The patients were interviewed about coronavirus disease 2019 (COVID-19) symptoms and history. Nasopharyngeal swabs were analyzed by SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR). SARS-CoV-2 IgG and IgA were measured concomitantly in patient sera by enzyme-linked immunosorbent assay.

Results: The risk of severe COVID-19 according to 2 recent scores differed among the analyzed patients. All patients were well educated about their presumed higher risk of a severe COVID-19 and described performing self-isolation wherever possible. Nevertheless, 20 patients reported contact with someone suspected of having COVID-19 or who tested positive shortly thereafter (18%). Despite this relatively high exposure, no clinically relevant case of COVID-19 was reported. Though SARS-CoV-2 IgG and IgA were found in 3 patients (3%); 2 patients were asymptomatic and only 1 had mild COVID-19 symptoms and positive RT-PCR 4 weeks earlier. There were no occult SARS-CoV-2 infections, as demonstrated by negative PCR tests.

Conclusion: Despite the high exposure level, the incidence of COVID-19 remained very low. Because of the differences in COVID-19 risk, balancing risk exposure and quality of life should be recommended.
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http://dx.doi.org/10.1016/j.transproceed.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833920PMC
May 2021

Pan-Genotype Pre-Exposure Prophylaxis (PrEP) Allows Transplantation of HCV-Positive Donor Kidneys to Negative Transplant Recipients.

J Clin Med 2020 Dec 29;10(1). Epub 2020 Dec 29.

Department of Nephrology and Intensive Medical Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

Transplant candidates are facing incremental mortality risks on the waiting list. Here, we report a novel strategy to expand the donor pool by including hepatitis C seropositive (HCV+) donors. We investigated a pre-exposure prophylactic (PrEP) treatment with direct-acting antivirals (DAA) to allow transplantation for HCV seronegative (HCV-) kidney transplant recipients (KTR) with the aim to prevent HCV infection post transplantation. In this prospective trial, a pan-genotypic PrEP with daclatasvir and sofosbuvir once daily for 12 week was administered at transplantation. The primary endpoint sustained virological negativity (SVN) 12 weeks after the end of PrEP. Seven patients received a transplantation from four HCV+ donors. Accumulated waiting time was 70 ± 31.3 months already. Of note, study subjects underwent transplantation 24.7 ± 16.1 days after given consent. All KTR developed excellent graft function without any rejection episodes. One patient died with a functioning graft due to sepsis 13 months after transplantation. PrEP demonstrated efficacy with no signs of HCV transmission with excellent tolerability. Two out of four HCV+ donors were viremic at the time of explantation. Interestingly, KTR developed HCV antibodies also from non viramic donors. The acceptance of HCV+ donor was safe and reduced waiting time under the protection of PrEP DAA in kidney transplantation.
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http://dx.doi.org/10.3390/jcm10010089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796396PMC
December 2020

The relationship between proteinuria and allograft survival in patients with transplant glomerulopathy: a retrospective single-center cohort study.

Transpl Int 2021 02 6;34(2):259-271. Epub 2020 Dec 6.

Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.

Proteinuria and transplant glomerulopathy (TG) are common in kidney transplantation. To date, there is limited knowledge regarding proteinuria in different types of TG and its relationship to allograft survival. A retrospective cohort analysis of TG patients from indication biopsies was performed to investigate the relationship of proteinuria, histology, and graft survival. One hundred and seven (57.5%) out of 186 TG patients lost their grafts with a median survival of 14 [95% confidence interval (CI) 10-22] months after diagnosis. Proteinuria ≥1 g/24 h at the time of biopsy was detected in 87 patients (46.8%) and the median of proteinuria was 0.89 (range 0.05-6.90) g/24 h. TG patients with proteinuria ≥1 g/24 h had worse 5-year graft survival (29.9% vs. 53.5%, P = 0.001) compared with proteinuria <1 g/24 h. Proteinuria was associated with graft loss in univariable Cox regression [hazard ratio (HR) 1.25, 95% CI, 1.11-1.41, P < 0.001], and in multivariable analysis (adjusted HR 1.26, 95% CI 1.11-1.42, P < 0.001) independent of other risk factors including creatinine at biopsy, positive C4d, history of rejection, and Banff lesion score mesangial matrix expansion. In this cohort of TG patients, proteinuria at indication biopsy is common and associated with a higher proportion of graft loss.
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http://dx.doi.org/10.1111/tri.13787DOI Listing
February 2021

Low Seroprevalence of SARS-CoV-2 Antibodies during Systematic Antibody Screening and Serum Responses in Patients after COVID-19 in a German Transplant Center.

J Clin Med 2020 Oct 23;9(11). Epub 2020 Oct 23.

Department of Nephrology and Medical Intensive Care, Charité- Universitätsmedizin Berlin, 13353 Berlin, Germany.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 denotes a global health issue. Data regarding COVID-19 incidence in kidney transplant recipients (KTR) are sparse. From 19 March to 19 May 2020, we performed a systematic screening for COVID-19 in KTR. Tests included serum analysis for SARS-CoV-2 antibodies using S protein-based immunofluorescence, anti-SARS-CoV-2 S1 immunoglobulin G (IgG) and immunoglobulin A (IgA) enzyme-linked immunosorbent assays (ELISA), and/or quantitative reverse transcription polymerase chain reaction (qRT-PCR) from nasal-throat swabs. Outpatient serum samples from KTR with PCR confirmed COVID-19, and swab samples from recipients (+donors) undergoing kidney transplantation were analyzed. Out of 223 samples from outpatients, 13 patients were positive with solely anti-SARS-CoV-2-IgA and 3 with both anti-IgA and anti-IgG. In total, 53 patients were symptomatic in the past, but positive results could be found in both symptomatic and asymptomatic patients. After an in depth analysis using immunofluorescence and neutralization tests in 2 KTR, recent COVID-19 infection remained highly suspicious. Apart from outpatient visits, only 5 out of 2044 KTR were symptomatic and tested positive via PCR, of which 4 recovered and one died. All patients showed seroconversion during the course of the disease. This study demonstrated a low seroprevalence in a German KTR cohort, and seroconversion of IgA and IgG after COVID-19 could be demonstrated. Effective containment strategies enabled us to continue our transplant program.
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http://dx.doi.org/10.3390/jcm9113401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690804PMC
October 2020

eHealth in transplantation.

Transpl Int 2021 01 27;34(1):16-26. Epub 2020 Nov 27.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

eHealth ("electronic" Health) is a new field in medicine that has the potential to change medical care, increase efficiency, and reduce costs. In this review, we analyzed the current status of eHealth in transplantation by performing a PubMed search over the last 5 years with a focus on clinical studies for post-transplant care. We retrieved 463 manuscripts, of which 52 clinical reports and eight randomized controlled trials were identified. Most studies were on kidney (n = 19), followed by liver (n = 10), solid organ (n = 7), bone-marrow (n = 6), and lung transplantation (n = 6). Eleven articles included adolescents/children. Investigated eHealth features covered the whole spectrum with mobile applications for patients (n = 24) and video consultations (n = 18) being most frequent. Prominent topics for patient apps were self-management (n = 16), adherence (n = 14), symptom-reporting (11), remote monitoring of vital signs (n = 8), educational (n = 7), and drug reminder (n = 7). In this review, we discuss opportunities and strengths of such new eHealth solutions, the implications for successful implementation into the healthcare process, the human factor, data protection, and finally, the need for better evidence from prospective clinical trials in order to confirm the claims on better patient care, potential efficiency gains and cost savings.
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http://dx.doi.org/10.1111/tri.13778DOI Listing
January 2021

Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial.

BMJ 2020 10 21;371:m3734. Epub 2020 Oct 21.

Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany

Objective: To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model.

Design: Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13).

Setting: Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union).

Participants: Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9).

Interventions: CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×10 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48.

Main Outcome Measures: The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio.

Results: For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire.

Conclusions: The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies.

Trial Registration: NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).
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http://dx.doi.org/10.1136/bmj.m3734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576328PMC
October 2020

Microvascular inflammation is a risk factor in kidney transplant recipients with very late conversion from calcineurin inhibitor-based regimens to belatacept.

BMC Nephrol 2020 08 20;21(1):354. Epub 2020 Aug 20.

Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: In de novo kidney transplant recipients (KTR) treatment with belatacept has been established as a comparable option as maintenance immunosuppression, preferably as a strategy to convert from calcineurin inhibitor (CNI)- to belatacept-based immunosuppression. Switch to belatacept demonstrated improved renal function in patients with CNI-induced nephrotoxicity, but risk of transplant rejection and the development of donor-specific antibodies (DSA) are still a matter of debate. Only few data are available in patients at increased immunological risk and late after transplantation.

Methods: We analyzed 30 long-term KTR (including 2 combined pancreas-KTR) converted from CNI to belatacept > 60 months after transplantation with moderate to severe graft dysfunction (GFR ≤ 45 mL/min). Biopsies were classified according to the Banff 2015 criteria. Group differences were assessed in a univariate analysis using Mann Whitney U or Chi square test, respectively. Multivariate analysis of risk factors for treatment failure was performed using a binary logistic regression model including significant predictors from univariate analysis. Fifty-six KTR matched for donor and recipient characteristics were used as a control cohort remaining under CNI-treatment.

Results: Patient survival in belatacept cohort at 12/24 months was 96.7%/90%, overall graft survival was 76.7 and 60.0%, while graft survival censored for death was 79.3%/66.7%. In patients with functioning grafts, median GFR improved from 22.5 mL/min to 24.5 mL/min at 24 months. Positivity for DSA at conversion was 46.7%. From univariate analysis of risk factors for graft loss, GFR < 25 mL/min (p = 0.042) and Banff microvascular inflammation (MVI) sum score ≥ 2 (p = 0.023) at conversion were significant at 24 months. In the analysis of risk factors for treatment failure, a MVI sum score ≥ 2 was significant univariately (p = 0.023) and in a bivariate (p = 0.037) logistic regression at 12 months. DSA-positivity was neither associated with graft loss nor treatment failure. The control cohort had comparable graft survival outcomes at 24 months, albeit without increase of mean GFR in patients with functioning grafts (ΔGFR of - 3.6 ± 8.5 mL/min).

Conclusion: Rescue therapy with conversion to belatacept is feasible in patients with worsening renal function, even many years after transplantation. The benefit in patients with MVI and severe GFR impairment remains to be investigated.
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http://dx.doi.org/10.1186/s12882-020-01992-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439694PMC
August 2020

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 2. Management of H1-Antihistamine-Refractory Chronic Urticaria.

Allergy Asthma Immunol Res 2020 Sep;12(5):750-770

Department of Dermatology, School of Medicine, Eulji University, Daejeon, Korea.

Quite a few patients with chronic spontaneous urticaria (CSU) are refractory to H₁-antihistamines, even though the dose of H₁-antihistamines is increased up to 4-fold. CSU that is not controlled with H₁-antihistamines results in increased disease burden. Several immunomodulators have been used to manage these patients. The guidelines reported herein are connected to Part 1 of the KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children, and aimed to provide evidence-based recommendations for the management of H₁-antihistamine-refractory CSU. Part 2 focuses on the more commonly used additional treatment options for refractory CSU, including omalizumab, cyclosporine, leukotriene receptor antagonist, dapsone, methotrexate, and phototherapy. The evidence to support their efficacy, dosing, safety, and selection of these agents is systematically reviewed. To date, for patients with refractory CSU, the methodologically sound data to evaluate the use of omalizumab has been growing; however, the evidence of other immunomodulators and phototherapy is still insufficient. Therefore, an individualized stepwise approach with a goal of achieving complete symptom control and minimizing side effects can be recommended. Larger controlled studies are needed to elevate the level of evidence to select a rational therapeutic agent for patients with refractory CSU.
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http://dx.doi.org/10.4168/aair.2020.12.5.750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346997PMC
September 2020

Risk communication for labeling all ingredients in consumer products.

J Toxicol Environ Health A 2020 07 18;83(13-14):509-524. Epub 2020 Jun 18.

Global Product Stewardship, Research and Development, Singapore Innovation Center, Procter & Gamble (P&G) International Operations , Singapore.

The labeling of all ingredients contained in consumer products has been requested by consumers concerned regarding their safety. Consequently, regulatory agencies have set guidelines for industries on how to provide safety information regarding the ingredients in their products. However, discordant opinions were raised from stakeholders, resulting in the formation of a risk communication forum among industries, regulatory agencies, consumer groups, and academia. There are several methods that might be utilized to provide ingredient information to consumers: (1) listing all ingredients on the label of products, (2) providing major ingredients on the label of products, (3) presenting all ingredients on the websites of each manufacturer, and (4) listing major ingredients on the label of products and the remainder of ingredients (not on the label) on the websites. Each method might have its own advantages and disadvantages with respect to providing the information regarding the names of the ingredients used in consumer products to the consumers. A continuous risk communication forum might be an effective tool to facilitate an improved understanding of chemical information, toxicological science, regulatory guidelines, labeling methods, and consumers' concern. This study suggests that risk communication efforts may be helpful and a good opportunity for stakeholders to exchange opinions and reach a harmonious conclusion on labeling of consumer products ingredients.
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http://dx.doi.org/10.1080/15287394.2020.1780174DOI Listing
July 2020

Mucosal associated invariant T cells are differentially impaired in tolerant and immunosuppressed liver transplant recipients.

Am J Transplant 2021 01 28;21(1):87-102. Epub 2020 Jun 28.

Department for General, Visceral and Vascular Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Mucosal associated invariant T (MAIT-) cells represent a semi-invariant T cell population responsive to microbial vitamin B metabolite and innate cytokine stimulation, executing border tissue protection and particularly contributing to human liver immunity. The impact of immunosuppressants on MAIT cell biology alone and in context with solid organ transplantation has not been thoroughly examined. Here, we demonstrate that in vitro cytokine activation of peripheral MAIT cells from healthy individuals was impaired by glucocorticoids, whereas antigen-specific stimulation was additionally sensitive to calcineurin inhibitors. In liver transplant (LTx) recipients, significant depletion of peripheral MAIT cells was observed that was largely independent of the type and dosage of immunosuppression, equally applied to tolerant patients, and was reproducible in kidney transplant recipients. However, MAIT cells from tolerant LTx patients exhibited a markedly diminished ex vivo activation signature, associated with individual regain of functional competence toward antigenic and cytokine stimulation. Still, MAIT cells from tolerant and treated liver recipients exhibited high levels of PD1, accompanied by functional impairment particularly toward bacterial stimulation that also affected polyfunctionality. Our data suggest interlinked effects of primary liver pathology and immunosuppressive treatment on overall MAIT cell fitness after transplantation and propose their monitoring in context with tolerance induction protocols.
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http://dx.doi.org/10.1111/ajt.16122DOI Listing
January 2021

Assessment of PM-bound nitrogen-containing organic compounds (NOCs) during winter at urban sites in China and Korea.

Environ Pollut 2020 Oct 28;265(Pt B):114870. Epub 2020 May 28.

School of Earth Sciences and Environmental Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea. Electronic address:

In this study, ambient fine particles (PM) were collected in two urban cities in China and Korea (Beijing and Gwangju, respectively) simultaneously in January 2018. Analysis of the nonpolar and semipolar organic matter (OM) using atmospheric pressure photoionization (APPI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) revealed that compounds containing only C, H, and O (CHO) and those containing C, H, O, and N (CHON) accounted for more than 90% of the total intensity of the OM peaks. Higher proportions of CHON compounds were observed during days with abnormally high PM concentrations at both sites than on regular or non-event days. The proportion of CHON species at the Beijing site was not correlated with secondary ionic species (i.e., NO, SO, and NH) or gaseous components (i.e., O, NO, and SO). In contrast, the proportion of CHON species at the Gwangju site was positively correlated with the concentrations of particulate nitrate and ammonium ions, assuming that ambient ammonium nitrate plays a role in the atmospheric formation of nitrogen-containing organic compounds (NOCs) at the Gwangju site and that Gwangju is more strongly influenced by secondary aerosols than Beijing is. In particular, a significant proportion of the compounds observed at the Beijing site contained only C, H and N (CHN), while negligible amounts of CHN were detected at the Gwangju site. The CHN species in Beijing were identified as quinoline compounds and the corresponding -CH homologous series using complementary GC × GC-TOF MS analysis. These results suggest that NOCs and their -CH homologous series from primary emissions may be significant contributors to nonpolar and semipolar OM during winter in Beijing, while NOCs with high oxidation states, likely formed via ambient-phase nitrate-mediated reactions, may be the dominant OM constituents in Gwangju.
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http://dx.doi.org/10.1016/j.envpol.2020.114870DOI Listing
October 2020

Structural variation of humic-like substances and its impact on plant stimulation: Implication for structure-function relationship of soil organic matters.

Sci Total Environ 2020 Jul 6;725:138409. Epub 2020 Apr 6.

Department of Agricultural Chemistry and Food Science & Technology, Gyeongsang National University, Jinju 52828, Republic of Korea; IALS, Gyeongsang National University, Jinju 52828, Republic of Korea. Electronic address:

Here, five aromatic monomers, one bearing a long alkyl chain [3-pentadecylphenol (3-PP)], the second bearing a polycyclic aromatic hydrocarbon [dihydroxynaphthalene (DHN)], the third bearing an organic amine [l-3,4-dihydroxyphenylalanine (l-DOPA)], the fourth bearing a carboxylic acid [vanillic acid (VA)], and the fifth bearing a phenol [catechol (CA)] were oxidatively coupled to produce four humic-like substances (3-PP, DHN, l-DOPA, and CAVA products) to mimic the diverse organic architectures of natural humus. Analysis using several methods, including SEM, EPR, elemental analysis, FT-IR-ATR, C NMR and anti-oxidant capability, revealed that each of the monomeric structures was well incorporated into the corresponding humic-like substances. Seed germination acceleration and NaCl-involved abiotic stress resistance of Arabidopsis thaliana were then tested to determine whether the different structures resulted in different levels of plant stimulation. The l-DOPA, CAVA and DHN-based materials showed enhanced stimulatory activities compared with no treatment, whereas the effects of the 3-PP-based materials were meager. Interestingly, high-resolution (15 T) ESI FT-ICR mass spectrometry-based van Krevelen diagrams clearly showed that the presence of molecules with H/C and O/C ratios ranging from 0.5 to 1.0 and 0.2 to 0.4, respectively, could be connected with such biological actions. Here, the l-DOPA sample showed the highest content of such molecules, followed by the CAVA, DHN and 3-PP samples. Next, the ability of l-DOPA and CAVA products to induce resistance in A. thaliana to a pathogen-related biotic stress was tested to confirm whether the proposed molecular features are associated with multi-stimulatory actions on plants. The expression level of pathogenesis-related protein 1 and inspection of plant morphology clearly revealed that both the l-DOPA and CAVA products stimulate plants to respond to biotic stresses. Size-exclusion chromatography together with NMR and IR data of both the materials strongly suggests that lignin-like supramolecular assemblages play an important role in versatile biological activities of humus.
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http://dx.doi.org/10.1016/j.scitotenv.2020.138409DOI Listing
July 2020

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 1. Definition, Methodology and First-line Management.

Allergy Asthma Immunol Res 2020 Jul;12(4):563-578

Department of Dermatology, Seoul St. Mary's Hospital, Brain Korea 21 PLUS Project for Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Chronic spontaneous urticaria (CSU) is defined as the occurrence of spontaneous wheals, angioedema, or both for >6 weeks in the absence of specific causes. It is a common condition associated with substantial disease burden both for affected individuals and societies in many countries, including Korea. CSU frequently persists for several years and requires high-intensity treatment; therefore, patients experience deteriorations in quality of life and medication-associated complications. During the last decade, there have been major advances in the pharmacological treatment of CSU and there is an outstanding need for evidence-based guidelines that reflect clinical practice in Korea. The guidelines reported here represent a joint initiative of the Korean Academy of Asthma, Allergy and Clinical Immunology and the Korean Dermatological Association, and aim to provide evidence-based guidance for the management of CSU in Korean adults and children. In Part 1, disease definition, guideline scope and development methodology as well as evidence-based recommendations on the use of antihistamines and corticosteroids are summarized.
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http://dx.doi.org/10.4168/aair.2020.12.4.563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224993PMC
July 2020

Specific circulating microRNAs during hepatitis E infection can serve as indicator for chronic hepatitis E.

Sci Rep 2020 03 24;10(1):5337. Epub 2020 Mar 24.

Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany.

Hepatitis E virus (HEV) genotypes 3 and 4 (HEV-3, HEV-4) infections are an emerging public health issue in industrialized countries. HEV-3 and -4 are usually self-limiting but can progress to chronic hepatitis E in immunocompromised individuals. The molecular mechanisms involved in persistent infections are poorly understood. Micro RNAs (miRNAs) can regulate viral pathogenesis and can serve as novel disease biomarkers. We aimed to explore the modulation of serum miRNAs in patients with acute (AHE) and chronic (CHE) hepatitis E. Both AHE- and CHE-patients exhibited high viral loads (median 3.23E + 05 IU/mL and 2.11E + 06 IU/mL, respectively) with HEV-3c being the predominant HEV-genotype. Expression analysis of liver-specific serum miRNAs was performed using real-time PCR. miR-99a-5p, miR-122-5p, and miR-125b-5p were upregulated in AHE (4.70-5.28 fold) and CHE patients (2.28-6.34 fold), compared to HEV-negative controls. Notably, miR-192-5p was increased 2.57 fold while miR-125b-5p was decreased 0.35 fold in CHE but not in AHE patients. Furthermore, decreased miR-122-5p expression significantly correlates with reduced liver transaminases in CHE patients. To our knowledge, this marks the first investigation concerning the regulation of circulating liver-specific miRNAs in acute and chronic HEV infections. We found that miR-125b-5p, miR-192-5p, and miR-99a-5p may prove useful in the diagnosis of chronic hepatitis E.
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http://dx.doi.org/10.1038/s41598-020-62159-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093451PMC
March 2020

Rituximab-Containing Treatment Regimens May Imply a Long-Term Risk for Difficult-To-Treat Chronic Hepatitis E.

Int J Environ Res Public Health 2020 01 3;17(1). Epub 2020 Jan 3.

Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, CVK, 13353 Berlin, Germany.

Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries which is usually characterized by a self-limited course. However, there is an increased risk of HEV persistence in immunocompromised risk populations, comprising patients following solid organ transplantation or hematological malignancies. Recently, chronic HEV infection following rituximab-containing treatment regimens has been described. Here we report five patients with chronic hepatitis E after prior rituximab therapy for various indications. We determined the immunological characteristics of these patients and analyzed the development of ribavirin (RBV) treatment failure-associated mutations in the HEV genome. One patient became chronically HEV-infected 110 months after administration of rituximab (RTX). Immunological characterization revealed that all patients exhibited significant hypogammaglobulinemia and CD4+ T cell lymphopenia. One patient permanently cleared HEV following weight-based ribavirin treatment while three patients failed to reach a sustained virological response. In depth mutational analysis confirmed the presence of specific mutations associated with RBV treatment failure in these patients. Our cases indicate that rituximab-containing treatment regimens might imply a relevant risk for persistent HEV infection even years after the last rituximab application. Moreover, we provide further evidence to prior observations suggesting that chronically HEV infected patients following RTX-containing treatment regimens might be difficult to treat.
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http://dx.doi.org/10.3390/ijerph17010341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982013PMC
January 2020

The TreaT-Assay: A Novel Urine-Derived Donor Kidney Cell-Based Assay for Prediction of Kidney Transplantation Outcome.

Sci Rep 2019 12 13;9(1):19037. Epub 2019 Dec 13.

Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Donor-reactive immunity plays a major role in rejection after kidney transplantation, but analysis of donor-reactive T-cells is not applied routinely. However, it has been shown that this could help to identify patients at risk of acute rejection. A major obstacle is the limited quantity or quality of the required allogenic stimulator cells, including a limited availability of donor-splenocytes or an insufficient HLA-matching with HLA-bank cells. To overcome these limitations, we developed a novel assay, termed the TreaT (Transplant reactive T-cells)-assay. We cultivated renal tubular epithelial cells from the urine of kidney transplant patients and used them as stimulators for donor-reactive T-cells, which we analyzed by flow cytometry. We could demonstrate that using the TreaT-assay the quantification and characterization of alloreactive T-cells is superior to other stimulators. In a pilot study, the number of pre-transplant alloreactive T-cells negatively correlated with the post-transplant eGFR. Frequencies of pre-transplant CD161 alloreactive CD4 T-cells and granzyme B producing alloreactive CD8 T-cells were substantially higher in patients with early acute rejection compared to patients without complications. In conclusion, we established a novel assay for the assessment of donor-reactive memory T-cells based on kidney cells with the potential to predict early acute rejection and post-transplant eGFR.
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http://dx.doi.org/10.1038/s41598-019-55442-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911059PMC
December 2019

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

Clin Infect Dis 2020 08;71(5):1204-1211

Department of Nephrology, CHU Rouen, Rouen, France.

Background: Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response.

Methods: Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months.

Results: After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event.

Conclusions: This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.
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http://dx.doi.org/10.1093/cid/ciz953DOI Listing
August 2020

Shikimic acid, a mannose bioisostere, promotes hair growth with the induction of anagen hair cycle.

Sci Rep 2019 11 18;9(1):17008. Epub 2019 Nov 18.

Department of Dermatology, College of Medicine, Seoul National University, Seoul, Republic of Korea.

Shikimic acid (SA) has recently been found to be a major component of plant stem cells. The exact effects of SA on human hair follicles (HFs) is unknown. The purpose of this study was to examine the effects of SA on hair growth. We investigated the effect of SA on an in vivo C57BL/6 mouse model. We examined the expression of mannose receptor (MR), which is a known receptor of SA, in human HFs and the effect of SA on human dermal papilla cells (hDPCs), outer root sheath cells (hORSCs), and on ex vivo human hair organ culture. SA significantly prolonged anagen hair growth in the in vivo mouse model. We confirmed expression of the MR in human HFs, and that SA increased the proliferation of hDPCs and hORSCs. It was found that SA enhanced hair shaft elongation in an ex vivo human hair organ culture. SA treatment of hDPCs led to increased c-myc, hepatocyte growth factor, keratinocyte growth factor and vascular endothelial growth factor levels and upregulation of p38 MAPK and cAMP response element-binding protein levels. Our results show that SA promotes hair growth and may serve as a new therapeutic agent in the treatment of alopecia.
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http://dx.doi.org/10.1038/s41598-019-53612-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861222PMC
November 2019
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