Publications by authors named "Chiara Cantarelli"

24 Publications

  • Page 1 of 1

Erythropoietin Reduces Auto- and Allo-Antibodies By Inhibiting T Follicular Helper Cell Differentiation.

J Am Soc Nephrol 2021 Jul 14. Epub 2021 Jul 14.

P Cravedi, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, United States

While high affinity IgG auto- and allo-antibodies are important drivers of kidney inflammation that can result in end stage kidney disease, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown. We assessed the impact and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell-dependent and T-independent, antibody formation using culture systems, murine models of organ transplantation and lupus nephritis, and mice conditionally deficient for the EPOR expressed on T cells or B cells. In wild type mice, recombinant EPO inhibited primary, T cell-dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T-independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell-, but not B cell-, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helpers (T). and experiments showed that EPO directly prevented T differentiation and function via a STAT5-dependent mechanism that reduces CD4+ T cell expression of In lupus models, EPO reduced T, GC B cells, and autoantibody production and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. studies verified that EPO prevents differentiation of human T cells. Our findings newly demonstrate that EPO inhibits T-dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney.
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http://dx.doi.org/10.1681/ASN.2021010098DOI Listing
July 2021

T Cell Exhaustion in Organ Transplantation.

Transplantation 2021 Jun 9. Epub 2021 Jun 9.

Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy UO Nefrologia, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts Division of Nephrology, Massachusetts General Hospital, Harvard Medical School Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Exhaustion of T cells occurs in response to chronic exposure to self and foreign antigens. It limits T cell capacity to proliferate and produce cytokines, leading to an impaired ability to clear chronic infections or eradicate tumors. T cell exhaustion is associated with a specific transcriptional, epigenetic, and metabolic program and characteristic cell surface markers' expression. Recent studies have begun to elucidate the role of T cell exhaustion in transplant. Higher levels of exhausted T cells have been associated with better graft function in kidney transplant recipients. In contrast, reinvigorating exhausted T cells by immune checkpoint blockade therapies, while promoting tumor clearance, increases the risk of acute rejection. Lymphocyte depletion and high alloantigen load have been identified as major drivers of T cell exhaustion. This could account, at least in part, for the reduced rates of acute rejection in organ transplant recipients induced with thymoglobulin and for the pro-tolerogenic effects of a large organ such as the liver. Amongst the drugs that are widely-used for maintenance immunosuppression, calcineurin inhibitors have a contrasting inhibitory effect on exhaustion of T cells, while the influence of mTOR inhibitors is still unclear. Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance. Supplemental Visual Abstract; http://links.lww.com/TP/C250.
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http://dx.doi.org/10.1097/TP.0000000000003851DOI Listing
June 2021

Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes.

J Clin Med 2021 Apr 2;10(7). Epub 2021 Apr 2.

Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.
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http://dx.doi.org/10.3390/jcm10071484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038198PMC
April 2021

Erythropoietin in Lupus: Unanticipated Immune Modulating Effects of a Kidney Hormone.

Front Immunol 2021 16;12:639370. Epub 2021 Mar 16.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease with variable clinical presentation, typically characterized by a relapsing-remitting course. SLE has a multifactorial pathogenesis including genetic, environmental, and hormonal factors that lead to loss of tolerance against self-antigens and autoantibody production. Mortality in SLE patients remains significantly higher than in the general population, in part because of the limited efficacy of available treatments and the associated toxicities. Therefore, novel targeted therapies are urgently needed to improve the outcomes of affected individuals. Erythropoietin (EPO), a kidney-produced hormone that promotes red blood cell production in response to hypoxia, has lately been shown to also possess non-erythropoietic properties, including immunomodulatory effects. In various models of autoimmune diseases, EPO limits cell apoptosis and favors cell clearance, while reducing proinflammatory cytokines and promoting the induction of regulatory T cells. Notably, EPO has been shown to reduce autoimmune response and decrease disease severity in mouse models of SLE. Herein, we review EPO's non-erythropoietic effects, with a special focus on immune modulating effects in SLE and its potential clinical utility.
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http://dx.doi.org/10.3389/fimmu.2021.639370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007959PMC
March 2021

Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring.

Kidney Int 2021 01 9;99(1):227-237. Epub 2020 Nov 9.

Department of Medicine, Renal Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels.
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http://dx.doi.org/10.1016/j.kint.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833801PMC
January 2021

Kidney Failure Associates With T Cell Exhaustion and Imbalanced Follicular Helper T Cells.

Front Immunol 2020 29;11:583702. Epub 2020 Sep 29.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Individuals with kidney failure are at increased risk of cardiovascular events, as well as infections and malignancies, but the associated immunological abnormalities are unclear. We hypothesized that the uremic milieu triggers a chronic inflammatory state that, while accelerating atherosclerosis, promotes T cell exhaustion, impairing effective clearance of pathogens and tumor cells. Clinical and demographic data were collected from 78 patients with chronic kidney disease (CKD) ( = 42) or end-stage kidney disease (ESKD) ( = 36) and from 18 healthy controls (HC). Serum cytokines were analyzed by Luminex. Immunophenotype of T cells was performed by flow cytometry on peripheral blood mononuclear cells. ESKD patients had significantly higher serum levels of IFN-γ, TNF-α, sCD40L, GM-CSF, IL-4, IL-8, MCP-1, and MIP-1β than CKD and HC. After mitogen stimulation, both CD4 and CD8 T cells in ESKD group demonstrated a pro-inflammatory phenotype with increased IFN-γ and TNF-α, whereas both CKD and ESKD patients had higher IL-2 levels. CKD and ESKD were associated with increased frequency of exhausted CD4 T cells (CD4KLRG1PD1CD57) and CD8 T cells (CD8KLRG1PD1CD57), as well as anergic CD4 T cells (CD4KLRG1PD1CD57) and CD8 T cells (CD8KLRG1PD1CD57). Although total percentage of follicular helper T cell (T) was similar amongst groups, ESKD had reduced frequency of T (CCR6CXCR3CXCR5PD1CD4CD8), but increased T (CCR6CXCR3CXCR5PD1CD4CD8), and plasmablasts (CD3CD56CD19CD27CD38CD138). In conclusion, kidney failure is associated with pro-inflammatory markers, exhausted T cell phenotype, and upregulated T, especially in ESKD. These immunological changes may account, at least in part, for the increased cardiovascular risk in these patients and their susceptibility to infections and malignancies.
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http://dx.doi.org/10.3389/fimmu.2020.583702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552886PMC
June 2021

A Comprehensive Phenotypic and Functional Immune Analysis Unravels Circulating Anti-Phospholipase A2 Receptor Antibody Secreting Cells in Membranous Nephropathy Patients.

Kidney Int Rep 2020 Oct 1;5(10):1764-1776. Epub 2020 Aug 1.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Introduction: Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited.

Methods: We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non-immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq).

Results: After adjusting for multiple testing, plasma cells and regulatory B cells (B) were significantly higher ( < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels ( = 0.042) and were associated with disease activity. -expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies ( < 0.001) in MN patients. Tumor necrosis factor-α (TNF-α) was the only significantly increased cytokine in MN patients ( < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire.

Conclusion: This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.
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http://dx.doi.org/10.1016/j.ekir.2020.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569696PMC
October 2020

Ultrasound to address medullary sponge kidney: a retrospective study.

BMC Nephrol 2020 10 12;21(1):430. Epub 2020 Oct 12.

U.O. Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Medicina e Chirurgia, Università di Parma, Via Gramsci 14, 43126, Parma, Italy.

Background: Medullary sponge kidney (MSK) is a rare disease characterized by cystic dilatation of papillary collecting ducts. Intravenous urography is still considered the gold standard for diagnosis. We identified a cohort of patients from our outpatient clinic with established diagnosis of MSK to outline some ultrasonographic characteristics that may help establish a diagnosis.

Methods: We conducted a retrospective study of patients seen between January 1st 2009 and January 1st 2019 in our clinic. Out of 4321 patients, 18 had a diagnosis of MSK. We reviewed their clinical and family history, laboratory data and imaging studies. Specifically, we focused on ultrasound imaging.

Results: Patients were referred to our outpatient clinic because of renal impairment (44%), family history of nephropathy (17%), nephrolithiasis or an established diagnosis of MSK (39%). Seventy-two percent of patients presented with chronic kidney disease, 22% required hemodialysis. Urinary tract infections (44%), nephrolithiasis (33%), microscopic hematuria (50%) and proteinuria (44%) were reported. Seven patients underwent computed tomography; all of them received ultrasound. Ultrasound examination showed bilateral renal cysts, usually small and located in the renal medulla, and microcalcifications located in the medulla or within the cysts.

Conclusion: We identified a peculiar tetrad associated with MSK: 1) hypoechoic medullary areas, 2) hyperechoic spots, 3) microcystic dilatation of papillary zone, 4) multiple calcifications (linear, small stones or calcified intracystic sediment) in each papilla. The presence of this diagnostic tetrad, added to laboratory data and clinical history, could be helpful in the differential diagnosis to identify patients with MSK.
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http://dx.doi.org/10.1186/s12882-020-02084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552549PMC
October 2020

Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis.

J Exp Med 2020 09;217(9)

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β-induced podocyte injury, potentially identifying new therapeutic targets.
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http://dx.doi.org/10.1084/jem.20191699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478737PMC
September 2020

Pneumococcal Polysaccharide Vaccine Ameliorates Murine Lupus.

Front Immunol 2019 20;10:2695. Epub 2019 Nov 20.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Current guidelines encourage administering pneumococcal vaccine Prevnar-13 to patients with lupus, but whether such vaccinations affect disease severity is unclear. To address this issue, we treated 3-month-old MRL- mice, that spontaneously develop a lupus-like syndrome, with Prevnar-13 or vehicle control. After 3 months, we quantified circulating anti-Pneumococcal polysaccharide capsule (PPS) antibodies and signs of disease severity, including albuminuria, renal histology and skin severity score. We also compared immunophenotypes and function of T and B cells from treated and untreated animals. Prevnar-13 elicited the formation of anti-pneumococcal IgM and IgG. Prevnar-13 treated animals showed reduced albuminuria, renal histological lesions, and milder dermatitis compared to vehicle-treated controls. Mitigated disease severity was associated with reduced and increased T follicular helper cells (T) and T follicular regulatory cells (T), respectively, in Prevnar-treated animals. T cells from Prevnar-13 vaccinated mice showed differential cytokine production after aCD3/aCD28 stimulation, with significantly decreased IL-17 and IL-4, and increased IL-10 production compared to non-vaccinated mice. In conclusion, pneumococcal vaccination elicits anti-pneumococcal antibody response and ameliorates disease severity in MRL- mice, which associates with fewer T and increased T. Together, the data support use of Prevnar vaccination in individuals with SLE.
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http://dx.doi.org/10.3389/fimmu.2019.02695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879550PMC
November 2020

Immune-Monitoring Disease Activity in Primary Membranous Nephropathy.

Front Med (Lausanne) 2019 8;6:241. Epub 2019 Nov 8.

Experimental Nephrology Laboratory, Biomedical Research Institute of Bellvitge (IDIBELL), Barcelona, Spain.

Primary membranous nephropathy (MN) is a glomerular disease mediated by autoreactive antibodies, being the main cause of nephrotic syndrome among adult patients. While the pathogenesis of MN is still controversial, the detection of autoantibodies against two specific glomerular antigens, phospholipase A2 receptor (PLAR) and thrombospondin type 1 domain containing 7A (THSD7A), together with the beneficial effect of therapies targeting B cells, have highlighted the main role of autoreactive B cells driving this renal disease. In fact, the detection of PLAR-specific IgG4 antibodies has resulted in a paradigm shift regarding the diagnosis as well as a better prediction of the progression and recurrence of primary MN. Nevertheless, some patients do not show remission of the nephrotic syndrome or do rapidly recur after immunosuppression withdrawal, regardless the absence of detectable anti-PLAR antibodies, thus highlighting the need of other immune biomarkers for MN risk-stratification. Notably, the exclusive evaluation of circulating antibodies may significantly underestimate the magnitude of the global humoral memory immune response since it may exclude the role of antigen-specific memory B cells. Therefore, the assessment of PLAR-specific B-cell immune responses using novel technologies in a functional manner may provide novel insight on the pathogenic mechanisms of B cells triggering MN as well as refine current immune-risk stratification solely based on circulating autoantibodies.
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http://dx.doi.org/10.3389/fmed.2019.00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856075PMC
November 2019

[The accuracy of hospital discharge records and their use in identifying and staging chronic kidney disease].

G Ital Nefrol 2019 Sep 24;36(5). Epub 2019 Sep 24.

UO Nefrologia, Dialisi e Ipertensione, Ospedale S.Orsola-Malpighi, Bologna.

Administrative databases contain precious information that can support the identification of specific pathologies. Specifically, chronic kidney disease (CKD) patients could be identified using hospital discharge records (HDR); these should contain information on the CKD stage using subcategories of the ICD9-CM classification's 585 code (subcategories can be expressed just by adding a fourth digit to this code). To verify the accuracy of HDR data regarding the coding of CKD collected in the Italian region Emilia-Romagna, we analyzed the HDR records of patients enrolled in the PIRP project, which could easily be matched with eGFR data obtained through laboratory examinations. The PIRP database was used as the gold standard because it contains data on CKD patients followed up since 2004 in thirteen regional nephrology units and includes data obtained from reliable and homogeneous laboratory measurement. All HDR of PIRP patients enrolled between 2009 and 2017 were retrieved and matched with available laboratory data on eGFR, collected within 15 days before or after discharge. We analyzed 4.168 HDR, which were classified as: a) unreported CKD (n=1.848, 44.3%); b) unspecified CKD, when code 585.9 (CKD, not specified) or 586 was used (n=446, 10.7%); c) wrong CKD (n=833, 20.0%); d) correct CKD (n=1041, 25.0%). We noticed the proportion of unreported CKD growing from 32.9% in 2009 to 56.6% in 2017, and the correspondent proportion of correct CKDs decreasing from 25.4% to 22.3%. Across disciplines, Nephrology showed the highest concordance (69.1%) between the CKD stage specified in the HDRs and the stage reported in the matched laboratory exam, while none of the other disciplines, except for Geriatrics, reached 20% concordance. When the CKD stage was incorrectly coded, it was generally underestimated; among HDRs with unreported or unspecified CKD at least half of the discharges were matched with lab exams reporting CKD in stage 4 or 5. We found that the quality of CKD stage coding in the HDR record database was very poor, and insufficient to identify CKD patients unknown to nephrologists. Moreover, the growing proportion of unreported CKD could have an adverse effect on patients' timely referral to a nephrologist, since general practitioners might remain unaware of their patients' illness. Actions aimed at improving the training of the operators in charge of HDRs compilation and, most of all, at allowing the exploitation of the informative potential of HDRs for epidemiological research are thus needed.
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September 2019

[Non erythropoietic effects of Erythropoietin].

G Ital Nefrol 2019 Sep 24;36(5). Epub 2019 Sep 24.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Over the past two decades it has emerged that, in addition to erythropoietic activity, erythropoietin (EPO) has numerous other functions, including neuro-protective, anti-apoptotic, antioxidant, angiogenetic and immunomodulatory ones. EPO interacts with two different forms of its receptor (EPOR): a homodimer receptor, responsible for the erythropoietic effects, and a heterodimer receptor, responsible for the non-erythropoietic effects. The effects on the heterodimer receptor are responsible for EPO-induced prolongation of organ transplant survival in mice and humans. The development of new molecules that selectively target the heterodimer EPOR is allowing to test the effect of long-term treatments, without the possible complications related to the increased hematocrit.
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September 2019

Circulating B Cells With Memory and Antibody-Secreting Phenotypes Are Detectable in Pediatric Kidney Transplant Recipients Before the Development of Antibody-Mediated Rejection.

Transplant Direct 2019 Sep 8;5(9):e481. Epub 2019 Aug 8.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Development of anti-human leukocyte antigen donor-specific antibodies (DSAs) is associated with antibody-mediated rejection (AMR) and reduced allograft survival in kidney transplant recipients. Whether changes in circulating lymphocytes anticipate DSA or AMR development is unclear.

Methods: We used time-of-flight mass cytometry to analyze prospectively collected peripheral blood mononuclear cells (PBMC) from pediatric kidney transplant recipients who developed DSA (DSA-positive recipients [DSA], n = 10). PBMC were obtained at 2 months posttransplant, 3 months before DSA development, and at DSA detection. PBMC collected at the same time points posttransplant from recipients who did not develop DSA (DSA-negative recipients [DSA], n = 11) were used as controls.

Results: DSA and DSA recipients had similar baseline characteristics and comparable frequencies of total B and T cells. Within DSA recipients, there was no difference in DSA levels (mean fluorescence intensity [MFI]: 13 687 ± 4159 vs 11 375 ± 1894 in DSAAMR-positive recipients (AMR) vs DSAAMR-negative recipients (AMR), respectively; = 0.630), C1q binding (5 DSAAMR [100%] vs 4 DSAAMR [80%]; = 1.000), or C3d binding (3 DSAAMR [60%] vs 1 DSAAMR [20%]; = 0.520) between patients who developed AMR and those who did not. However, DSA patients who developed AMR (n = 5; 18.0 ± 3.6 mo post-DSA detection) had increased B cells with antibody-secreting (IgDCD27CD38; = 0.002) and memory (IgDCD27CD38; = 0.003) phenotypes compared with DSA and DSAAMR recipients at DSA detection.

Conclusions: Despite the small sample size, our comprehensive phenotypic analyses show that circulating B cells with memory and antibody-secreting phenotypes are present at DSA onset, >1 year before biopsy-proven AMR in pediatric kidney transplant recipients.
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http://dx.doi.org/10.1097/TXD.0000000000000914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739044PMC
September 2019

Immune responses towards bioengineered tissues and strategies to control them.

Curr Opin Organ Transplant 2019 10;24(5):582-589

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose Of Review: Research into development of artificial tissues and bioengineered organs to replace physiological functions of injured counterparts has highlighted a previously underestimated challenge for its clinical translatability: the immune response against biomaterials. Herein, we will provide an update and review current knowledge regarding this important barrier to regenerative medicine.

Recent Findings: Although a clear understanding of the immune reactivity against biomaterials remains elusive, accumulating evidence indicates that innate immune cells, primarily neutrophils and macrophages, play a key role in the initial phases of the immune response. More recently, data have shown that in later phases, T and B cells are also involved. The use of physicochemical modifications of biomaterials and cell-based strategies to modulate the host inflammatory response is being actively investigated for effective biomaterial integration.

Summary: The immune response towards biomaterials and bioengineered organs plays a crucial role in determining their utility as transplantable grafts. Expanding our understanding of these responses is necessary for developing protolerogenic strategies and delivering on the ultimate promise of regenerative medicine.
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http://dx.doi.org/10.1097/MOT.0000000000000688DOI Listing
October 2019

A Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy.

A careful management of antimicrobials is essential in the critically ill with acute kidney injury, especially if renal replacement therapy is required. Acute kidney injury may lead to clinically significant modifications of drugs' pharmacokinetic parameters, and the need for renal replacement therapy represents a further variable that should be considered to avoid inappropriate antimicrobial therapy. The most important pharmacokinetic parameters, useful to determine the significance of extracorporeal removal of a given drug, are molecular weight, protein binding, and distribution volume. In many cases, the extracorporeal removal of antimicrobials can be relevant, with a consistent risk of underdosing-related treatment failure and/or potential onset of bacterial resistance. It should also be taken into account that renal replacement therapies are often not standardized in critically ill patients, and their impact on plasma drug concentrations may substantially vary in relation to membrane characteristics, treatment modality, and delivered dialysis dose. Thus, in this clinical scenario, the knowledge of the pharmacokinetic and pharmacodynamic properties of different antimicrobial classes is crucial to tailor maintenance dose and/or time interval according to clinical needs. Finally, especially for antimicrobials known for a tight therapeutic range, therapeutic drug monitoring is strongly suggested to guide dosing adjustment in complex clinical settings, such as septic patients with acute kidney injury undergoing renal replacement therapy.
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http://dx.doi.org/10.1128/AAC.00583-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658763PMC
August 2019

Criteria for Living Donation from Marginal Donors: One, No One, and One Hundred Thousand.

Nephron 2019 20;142(3):227-232. Epub 2019 May 20.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA,

Context: The increasing need for kidney grafts has led to a progressive expansion in the selection criteria for deceased and living donors (LDs). While concerns regarding the use of organs from suboptimal deceased donors relate to the quality of the graft, donation from "marginal" LDs may pose potential harm to the donor. Subject of Review: Living kidney donation is a safe procedure, but is associated with a small risk of end-stage kidney disease in the long- term. When elderly subjects and those with comorbidities are considered, long-term post-donation data are missing, making decisions regarding donation from these populations challenging. Further, vague guidelines have led to a wide heterogeneity in the criteria for living donation from marginal donors across centers and individuals. A recent survey by Lafranca et al. [PLoS One 2017;12:e0181846] collected information from 331 members (mainly physicians) of the European Society of Transplantation regarding several expanded LD criteria. Median refusal rate for potential expanded criteria (ECD) LDs is 15% and the authors found significant differences across regions in Europe in the acceptance of donors with ECD. Some transplant specialists did also deviate from their own transplant center policy, mainly to consider donors with high body mass index. Second Opinion: The survey by Lafranca et al. [PLoS One 2017;12:e0181846] documents extreme variability in the criteria for marginal LD selection. Many centers are deviating from the few agreed upon guideline criteria and are considering individuals with hypertension and minors for kidney donation. Intriguingly, one-fourth of the surgeons even deviate occasionally from center policy, especially when the issue is donor obesity. By and large, these data indicate that transplant community has a generally open approach toward extension of criteria for living donation, but long-term follow-up studies are needed to draw solid conclusions and guidelines.
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http://dx.doi.org/10.1159/000500498DOI Listing
June 2020

T-cell exhaustion correlates with improved outcomes in kidney transplant recipients.

Kidney Int 2019 08 27;96(2):436-449. Epub 2019 Feb 27.

Department of Medicine, Division of Nephrology and Translational Transplant Research Center, Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Continuous antigen stimulation during chronic infection or malignancy can promote functional T cell silencing, a phenomenon called T cell exhaustion. The prevalence and impact of T cell exhaustion following organ transplantation, another immune stimulus with persistently high antigen load, are unknown. Here, we characterized serially collected peripheral blood mononuclear cells from 26 kidney transplant recipients using time-of-flight mass cytometry (CyTOF) to define distinct subsets of circulating exhausted T cells and their relationship to induction therapy and allograft function. We observed an increase in specific subsets of CD4 and CD8 exhausted T cells from pre-transplant to 6-months post-transplant, with greater increases in participants given anti-thymocyte globulin induction than in participants who received no induction or non-depleting induction. The percentages of exhausted T cells at 6 months correlated inversely with adenosine triphosphate (ATP) production (a surrogate of T cell function) and with allograft interstitial fibrosis. Guided by the CyTOF data, we delineated a PD-1CD57 phenotype for CD4 and CD8 exhausted T cells, and confirmed that these cells have limited capacity for cytokine secretion and ATP production. In an independent cohort of 50 kidney transplant recipients, we confirmed the predicted increase of PD-1CD57 exhausted T cells after lymphocyte-depleting induction therapy and its direct correlation with better allograft function. Our findings suggest that monitoring T cell exhaustion can be useful for post-transplant risk assessment and support the need to develop and test strategies aimed at augmenting T cell exhaustion following kidney transplantation.
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http://dx.doi.org/10.1016/j.kint.2019.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650324PMC
August 2019

Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease.

JCI Insight 2019 04 23;5. Epub 2019 Apr 23.

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

IL-17-producing CD4+ cells (TH17) are pathogenically linked to autoimmunity including to autoimmune kidney disease. Erythropoietin's (EPO) newly recognized immunoregulatory functions and its predominant intra-renal source suggested that EPO physiologically regulates TH17 differentiation, thereby serving as a barrier to the development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4+ T cells directly inhibits TH17 generation and promotes trans-differentiation of TH17 into IL-17-FOXP3+CD4+ T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL-17 and IL-23 receptor genes. In a murine model of TH17-dependent aristolochic acid (ArA)-induced, interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits TH17 formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4+ T cells abrogate, while absence of T cell-expressed EPO-R augments, TH17 induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and TH17 generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulate TH17 cells to limit expression of TH17-associated autoimmune kidney disease.
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http://dx.doi.org/10.1172/jci.insight.127428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542617PMC
April 2019

Erythropoietin, a multifaceted protein with innate and adaptive immune modulatory activity.

Am J Transplant 2019 09 25;19(9):2407-2414. Epub 2019 Apr 25.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Erythropoietin (EPO) is a glycoprotein produced mainly by the adult kidney in response to hypoxia and is the crucial regulator of red blood cell production. EPO receptors (EPORs), however, are not confined to erythroid cells, but are expressed by many organs including the heart, brain, retina, pancreas, and kidney, where they mediate EPO-induced, erythropoiesis-independent, tissue-protective effects. Some of these tissues also produce and locally release small amounts of EPO in response to organ injury as a mechanism of self-repair. Growing evidence shows that EPO possesses also important immune-modulating effects. Monocytes can produce EPO, and autocrine EPO/EPOR signaling in these cells is crucial in maintaining immunologic self-tolerance. New data in mice and humans also indicate that EPO has a direct inhibitory effect on effector/memory T cells, while it promotes formation of regulatory T cells. This review examines the nonerythropoietic effects of EPO, with a special emphasis on its modulating activity on innate immune cells and T cells and on how it affects transplant outcomes.
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http://dx.doi.org/10.1111/ajt.15369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711804PMC
September 2019

HCV-Associated Nephropathies in the Era of Direct Acting Antiviral Agents.

Front Med (Lausanne) 2019 8;6:20. Epub 2019 Feb 8.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Hepatitis C virus (HCV) infection is a systemic disorder that frequently associates with extrahepatic manifestations, including nephropathies. Cryoglobulinemia is a typical extrahepatic manifestation of HCV infection that often involves kidneys with a histological pattern of membranoproliferative glomerulonephritis. Other, less common renal diseases related to HCV infection include membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, fibrillary and immunotactoid glomerulopathy. Over the last decades, the advent of direct-acting antiviral therapies has revolutionized treatment of HCV infection, dramatically increasing the rates of viral clearance. In patients where antiviral therapy alone fails to induce renal disease remission add-on B-cell depleting agents represent an alternative to counteract the synthesis of pathogenic antibodies. Immunosuppressive therapies, such as steroids, alkylating agents, and plasma exchanges, may still represent an effective option to inhibit immune-complex driven inflammatory response, but the potentially associated increase of HCV replication and worsening of liver disease represent a serious limitation to their use.
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http://dx.doi.org/10.3389/fmed.2019.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376251PMC
February 2019

[Acute kidney injury as a risk marker for hospital readmission: a single-center pilot study in the general population of the Parma area].

G Ital Nefrol 2018 Dec;35(6)

Unità di Fisiopatologia dell'Insufficienza Renale Acuta e Cronica - Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma.

Acute Kidney Injury (AKI) is an important issue for the healthcare system, as it is associated with high mortality and increased risk of readmission, with consequent elevated healthcare resource utilization. We investigated the incidence of AKI based on the examination of the discharge cards of all patients admitted between January 1 2011 and December 31 2015 at the Parma University Hospital, as well as the frequency and type of 30-day hospital readmission in the patients discharged with a first AKI diagnosis (index admission). The mean pooled 5-year incidence of AKI was 2.4%. The mean frequency of 30-day readmission for any disease in patients discharged with a first AKI diagnosis in the selected time interval was 23.1%/year. The main four disease categories, as assessed by the Diagnosis Related Group (DRG) classification, responsible for patient 30-day readmission were a new AKI episode, heart failure, respiratory failure requiring or not requiring mechanical ventilation, and sepsis. The mean lenght of hospital stay of patients discharged with AKI as a principal or secondary diagnosis was 14.4 and 21.8 days, respectively. Based on the evaluation of administrative data from all hospital admissions at the Parma University Hospital in the 2011-2015 5-year period, we conclude that AKI represents a serious challenge for the healthcare system, with high short-term morbidity and increased resource utilization due to frequent hospital readmissions.
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December 2018

Noninvasive evaluation of muscle mass by ultrasonography of quadriceps femoris muscle in End-Stage Renal Disease patients on hemodialysis.

Clin Nutr 2019 06 19;38(3):1232-1239. Epub 2018 May 19.

Acute and Chronic Renal Failure Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy; Postgraduate School of Nephrology, Parma University, Parma, Italy. Electronic address:

Background & Aims: Protein-Energy Wasting (PEW) is a pathological condition of renal patients with advanced Chronic Kidney Disease characterized by a progressive reduction of energy and protein assets. Nutritional status assessment, especially for what concerns muscle mass, is essential for both the identification of patients at risk for the development of PEW, as well as monitoring the effects of nutritional interventions. Ultrasound methods are easily applicable at the bedside for quantitative assessment of skeletal muscle. The present study was aimed at evaluating quadriceps rectus femoris thickness (QRFT) and quadriceps vastus intermedius thickness (QVIT) in patients on chronic hemodialysis.

Methods: This was a prospective observational study. Three groups of adult patients were studied: young healthy subjects, well-nourished hospitalized patients with normal renal function, and End-Stage Renal Disease patients on hemodialysis (ESRD-HD). QRFT and QVIT were measured at two sites bilaterally (8 measures/patient) and were compared between groups, and also between subgroups of ESRD-HD patients stratified on the basis of conventional nutritional status parameters.

Results: We enrolled 35 healthy subjects, 30 hospitalized patients, and 121 ESRD-HD patients on hemodialysis. QRFT and QVIT of ESRD patients on hemodialysis were lower than those of both control groups (P < 0.001). After stratifying ESRD patients into subgroups based on nutritional variable cut-offs commonly used to define PEW in this clinical setting (BMI [≥ 23 vs <23 kg/m], albumin [≥3.8 vs <3.8 g/dL]) and malnutrition inflammation score (MIS) status (<6 vs ≥6), QRFT and QVIT of patients with worse nutritional status were significantly lower than those of well-nourished ESRD-HD patients (P value range: <0.001 to <0.05).

Conclusion: Skeletal muscle ultrasound is a simple and easily applicable bedside technique in the dialysis units, and could represent an adequate tool for the identification of patients with reduced muscle mass.
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http://dx.doi.org/10.1016/j.clnu.2018.05.004DOI Listing
June 2019
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