Anft, Moritz

Babel, Nina

Berger, Marc Moritz

Blazquez-Navarro, Arturo

Brenner, Thorsten

Dittmer, Ulf

Doevelaar, Adrian

Dolff, Sebastian

Hoelzer, Bodo

Konik, Margarete Justine

Meister, Toni Luise

Mittmann, Lisa

Or-Guil, Michal

Paniskaki, Krystallenia

Pfaender, Stephanie

Roch, Toralf

Seibert, Felix Sebastian

Steinmann, Eike

Stervbo, Ulrik

Tempfer, Clemens

Thieme, Constantin Joachim

Watzl, Carsten

Westhoff, Timm Henning

Witzke, Oliver

English

Institutional Repository of the Freie Universität Berlin

Vol.:(0123456789) Journal of Nephrology (2023) 36:199–202 https://doi.org/10.1007/s40620-022-01374-1RESEARCH LETTERImpact of low eGFR on the immune response against COVID‑19Arturo Blazquez‑Navarro1,2  · Lisa Mittmann3 · Constantin Joachim Thieme2,4 · Moritz Anft1 · Krystallenia Paniskaki1 · Adrian Doevelaar1 · Felix Sebastian Seibert1 · Bodo Hoelzer1 · Margarete Justine Konik3 · Marc Moritz Berger5 · Thorsten Brenner5 · Clemens Tempfer6 · Carsten Watzl7 · Toni Luise Meister8 · Stephanie Pfaender8 · Eike Steinmann8 · Sebastian Dolff3 · Ulf Dittmer9 · Oliver Witzke3 · Ulrik Stervbo1 · Toralf Roch1,2 · Michal Or‑Guil2 · Timm Henning Westhoff1 · Nina Babel1,2,4Received: 30 May 2022 / Accepted: 31 May 2022 / Published online: 2 July 2022 © The Author(s) 2022Patients with low renal function have an increased risk of critical COVID-19. While chronic kidney disease is associ-ated with impairment of the immune system, it is still not known whether their worse COVID-19 outcome can be explained by a weaker antiviral response or by systemic inflammation. Importantly, there is still no literature on the immunological characteristics of COVID-19 patients with low renal function, which could potentially explain their increased fatality rate. Here, we performed an observa-tional cohort study on 173 consecutively enrolled hospital-ized COVID-19 patients, a non-vaccinated cohort recruited in 2020, which was classified according to their estimated glomerular filtration rate (eGFR) at admission. We analysed the immunological differences between patients with low and normal renal function, including circulating T and B cell subsets, SARS-CoV-2 reactive T cells and serum cytokines in follow-up. For more details on the methods, see the Sup-plementary Methods.The patients were recruited (initial visit) at a median of 3 [IQR 1–6] days after the first positive PCR test. One hun-dred forty-three (82.7%) patients showed normal renal func-tion at admission (hereafter Normal-eGFR; eGFR > 60 ml/min/1.73m2), while 30 patients (17.3%) suffered from low renal function (Low-eGFR; < 60 ml/min/1.73m2). Low-eGFR patients had significantly higher age (P < 0.001; see Table S1) and Charlson comorbidity index (P = 0.002). Therefore, we controlled for these factors in our analyses employing multivariate regression, as explained in the Sup-plementary Methods. Twelve patients (7.3%) died during follow-up; the Normal-eGFR sub-cohort had 5 fatal cases (3.5%), while for Low-eGFR there were 7 (23.3%). The association between Low-eGFR and patient death was sig-nificant (P = 0.022), independently from confounders.Arturo Blazquez-Navarro and Lisa Mittmann contributed equally. * Nina Babel  nina.babel@charite.de1 Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Ruhr-University Bochum, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, North Rhine-Westphalia, Germany2 BIH Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany3 Department of Infectious Diseases, West-German Centre for Infectious Diseases, University Duisburg-Essen, University Hospital Essen, Essen, North Rhine-Westphalia, Germany4 Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany5 Department of Anaesthesiology and Intensive Care Medicine, West-German Centre for Infectious Diseases, University Duisburg-Essen, University Hospital Essen, Essen, North Rhine-Westphalia, Germany6 Department of Gynaecology and Obstetrics, Ruhr-University Bochum, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, North Rhine-Westphalia, Germany7 Department of Immunology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund (IfADo), Dortmund, North Rhine-Westphalia, Germany8 Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, North Rhine-Westphalia, Germany9 Institute for Virology, University Duisburg-Essen, University Hospital Essen, Essen, North Rhine-Westphalia, Germany200 Journal of Nephrology (2023) 36:199–2021 3We first analysed general immunological parame-ters: Almost all patients were lymphopenic (Fig. 1a). We observed significantly higher neutrophil counts among patients in the Low-eGFR group (Fig. 1b). Higher neutro-phil counts have been associated with increased COVID-19 severity [1]. Regarding the T cell subset, patients with low eGFR had higher levels of in vivo activated HLA-DR+  CD4+ and  CD8+ T cells, albeit without reaching statisti-cal significance (Figure S1). On the other hand, we found significantly increased levels for terminally differentiated  CD11a++CD28−CD57+ T cells among Low-eGFR at fol-low-up (Fig. 1c, d). These cells express markers of tissue migration  (CD11a++) and do not require costimulatory mol-ecules for activation  (CD28−). This is in line with previous Initial Follow−up0.01.02.03.0Lymphocytes (%)aInitial Follow−up0246810Neutrophiles (%)P  = 0.035bInitial Follow−up05102030CD11a++CD28−CD57+ among CD4+ (%)P  = 0.014cInitial Follow−up020406080100CD11a++CD28−CD57+ among CD8+ (%)P  = 0.040dInitial Follow−up0.000.100.200.30Anti−S−CD4p+CD154p+CD137+ among +CD4p+ (%)eInitial Follow−up0.00.20.40.60.8Anti−S−CD8p+CD137+ among +CD8p+ (%)f−20−1001020Low−eGFR Normal−eGFR∆IL−1β (pg/ml)gP  = 0.013−20−1001020Low−eGFR Normal−eGFR∆IFN−α2 (pg/ml)hP< 0.001−20−1001020Low−eGFR Normal−eGFR∆IFN−γ (pg/ml)iP< 0.001−600−200200600Low−eGFR Normal−eGFR∆MCP−1 (pg/ml)jP  = 0.005−100050100Low−eGFR Normal−eGFR∆IL−6 (pg/ml)kP< 0.001−40−2002040Low−eGFR Normal−eGFR∆IL−10 (pg/ml)lP< 0.001−100005001000Low−eGFR Normal−eGFR∆IL−18 (pg/ml)mP< 0.001 Normal−eGFR(>60 ml/min/1.73m2 )Low−eGFR(<60 ml/min/1.73m2 )201Journal of Nephrology (2023) 36:199–202 1 3studies that identified such alterations in COVID-19 critical versus less severe disease manifestations [2]. Furthermore, an increase in  CD28−CD57+ T cells has been observed repeatedly in a context of severe CKD [3]. These cells also expressed high levels of CD11a, a marker highly expressed in memory T cells and associated with activation and tissue migration [2].  CD11a++CD28−CD57+CD8+ T cells are asso-ciated with bystander activation in inflamed tissue, signifi-cantly contributing to tissue damage [4]. Higher frequencies of this cell subset might therefore contribute to the worse clinical outcome of patients with lower eGFR. Since these terminally differentiated cells are likely associated with age-ing and chronic antigen exposure, we analysed the T cell memory composition in the patient cohorts but did not find any significant differences between the sub-cohorts (Fig-ure S2). Finally, we did not find any significant differences between the study sub-cohorts for the SARS-CoV-2-specific T cell response (Fig. 1e, f) nor in the B cell compartment (Figure S3).We further examined the differences in the cytokine pro-files of the two sub-cohorts. While there were no significant differences in cytokine concentrations at either study visit (Figure S4), there was a significant decrease in the concen-tration of IL-1β, IFN-α2, IFN-γ, MCP-1, IL-6, IL-10 and IL-18 in the Normal-eGFR sub-cohort during follow-up, while the cytokine level remained unchanged in the Low-eGFR sub-cohort (Fig. 1g–m). We hypothesize that the lat-ter dynamics are the result of chronic systemic inflamma-tion. Previous studies on patients with senescent immunity demonstrate that chronic inflammation is associated with a higher mortality through infection [5]. Therefore, cytokine data suggest that patients with impaired kidney function might suffer from chronic inflammation, which could cause higher immunopathology and overall mortality.In summary, we present a characterization of the immune system of COVID-19 patients with reduced renal function. Here, low eGFR emerges as a factor associated with T cell immunosenescence and an altered inflammatory response. These immunological alterations could potentially explain the worse disease outcomes of patients with reduced renal function. Main limitations of our work include the low num-ber of patients within the Low-eGFR group, availability of sufficient samples, the differences in age and co-morbidities between the sub-cohorts and the fact that the cohort was recruited between spring and autumn 2020. Further, pro-spective studies with larger patient cohorts and long-term follow-up data are needed to confirm our observations.COVID-19, chronic kidney disease, renal function, immune system, immunosenescence.Supplementary Information The online version contains supplemen-tary material available at https:// doi. org/ 10. 1007/ s40620- 022- 01374-1.Acknowledgements We want to thank the patients who donated their blood samples and clinical data for this project.Funding Open Access funding enabled and organized by Projekt DEAL. This work was supported by grants from the German Federal Ministry for Education and Research (BMBF) e:KID (01ZX1612A) and NoChro (FKZ 13GW0338B), the Mercator Foundation, Germany (St-2018–0014) and SepsisDataNet (EFRE-0800984).Availability of data and material Limited data access requests can be sent to Nina Babel (nina.babel@charite.de).Code availability Not applicable.Declarations Conflict of interest The authors have no conflicts of interest.Ethical approval The study was approved by the ethical committee of the University Hospitals Bochum (20–6886) and Essen (20-9214-BO).Consent to participate Informed consent was obtained from all indi-vidual participants included in the study.Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.Fig. 1  Patients in the Low-eGFR sub-cohort demonstrated an altered immune system.  The figure depicts the levels of circulating immune subsets at the initial and follow-up visit (a–f), as well as the changes in serum cytokines between the two visits (g–m). For the immune subsets, peripheral blood from 57 patients, 41 from the Normal-eGFR sub-cohort (blue) and 16 from the Low-eGFR sub-cohort (red) was characterized. The figure depicts the frequencies of circulating lym-phocytes (a), neutrophils (b), terminally differentiated T cells (c, d) and T cells specific against the viral spike antigen (e–f) using mul-tiparametric flow cytometry. The P values were calculated controlling for differences in age and Charlson comorbidity index (see Statistical methods). In all cases, the left boxplots show the data for the initial visit, while the right boxplots depict the data at follow-up. The area shaded in grey represents the reference range for each parameter, if applicable. For the cytokine kinetics (g–m), 74 patients were ana-lysed, 61 Low-eGFR sub-cohort (red) and 13 Normal-eGFR sub-cohort (blue). The figure shows the change in cytokine levels between initial and follow-up for each patient, where a negative value means a decrease in concentration and vice versa. A dashed grey line marks the threshold of a null change between the visits. Importantly, the P value does not refer to a comparison between the two sub-cohorts, but to the significance of the change in cytokine concentrations within each sub-cohort. eGFR estimated glomerular filtration rate; IFN inter-feron; IL interleukin; MCP monocyte chemoattractant protein◂202 Journal of Nephrology (2023) 36:199–2021 3References 1. Kuri-Cervantes L, Pampena MB, Meng W, Rosenfeld AM, Ittner CAG, Weisman AR, Agyekum RS, Mathew D, Baxter AE, Vella LA, Kuthuru O, Apostolidis SA, Bershaw L, Dougherty J, Green-plate AR, Pattekar A, Kim J, Han N, Gouma S, Weirick ME, Arevalo CP, Bolton MJ, Goodwin EC, Anderson EM, Hensley SE, Jones TK, Mangalmurti NS, Luning Prak ET, Wherry EJ, Meyer NJ, Betts MR (2020) Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci Immunol. https:// doi. org/ 10. 1126/ sciim munol. abd71 14 2. 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Impact of low eGFR on the immune response against COVID-19

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Impact of low eGFR on the immune response against COVID-19

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