Publications by authors named "Paolo Cravedi"

164 Publications

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

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial.

PLoS Med 2021 Jun 24;18(6):e1003668. Epub 2021 Jun 24.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.

Methods And Findings: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.

Conclusions: In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.

Trial Registration: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
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http://dx.doi.org/10.1371/journal.pmed.1003668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224852PMC
June 2021

Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options.

Front Med (Lausanne) 2021 4;8:653634. Epub 2021 Jun 4.

Nephrology Department, Complejo Hospitalario de Navarra, Pamplona, Spain.

Hyperkalemia is one of the main electrolyte disorders in patients with chronic kidney disease (CKD). The prevalence of hyperkalemia increases as the Glomerular Filtration Rate (GFR) declines. Although chronic hyperkalemia is not a medical emergency, it can have negative consequences for the adequate cardio-renal management in the medium and long term. Hyperkalemia is common in patients on renin-angiotensin-aldosterone system inhibitors (RAASi) or Mineralocorticoid Receptor Antagonists (MRAs) and can affect treatment optimization for hypertension, diabetes mellitus, heart failure (HF), and CKD. Mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF compared with full RAASi dosing, and are the highest among patients who discontinue RAASis. The treatment of chronic hyperkalemia is still challenging. Therefore, in the real world, discontinuation or reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on RAASi therapy to enhance cardio and reno-protective effects. Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin over 50 years ago. Nowadays, two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) already approved by FDA and by the European Medicines Agency, have demonstrated their clinical efficacy in reducing serum potassium with a good safety profile. The use of the newer potassium binders may allow continuing and optimizing RAASi therapy in patients with hyperkalemia keeping the cardio-renal protective effect in patients with CKD and cardiovascular disease. However, further research is needed to address some questions related to potassium disorders (definition of chronic hyperkalemia, monitoring strategies, prediction score for hyperkalemia or length for treatment).
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http://dx.doi.org/10.3389/fmed.2021.653634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213200PMC
June 2021

Vaccines and Disease Relapses in Children with Nephrotic Syndrome.

Clin J Am Soc Nephrol 2021 06 11;16(6):937-938. Epub 2021 Jun 11.

Division of Nephrology, Dialysis, and Transplantation, Instituto di ricovero e cura a carattere scientifico (IRRCS) Instituto Giannina Gaslini Children's Hospital, Genoa, Italy

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http://dx.doi.org/10.2215/CJN.01890221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216624PMC
June 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

Corrigendum to "Erythropoietin administration expands regulatory T cells in patients with autoimmune hepatitis" [J. Autoimmun. 119C (2021) 102629].

J Autoimmun 2021 Jul 28;121:102665. Epub 2021 May 28.

Department of Internal Medicine, Northwestern University, Chicago, IL, USA; Northwestern Feinberg School of Medicine, Chicago, IL, USA; Division of Gastroenterology & Hepatology and Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jaut.2021.102665DOI Listing
July 2021

DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity.

J Clin Invest 2021 May;131(10)

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

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence-specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach1-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes.
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http://dx.doi.org/10.1172/JCI141279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121508PMC
May 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

Preventing Coronavirus Disease 2019 in Kidney Transplant Recipients: Where Should We Begin?

Nephron 2021 31;145(3):280-284. Epub 2021 Mar 31.

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

Context: Chronic immunosuppression is associated with an increased risk of opportunistic infections. Although kidney transplant recipients with coronavirus disease 2019 (COVID-19) have higher mortality than the general population, data on their risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are unknown. Subject of Review: A recent single-center screening study from the UK (Transplantation. 2021 Jan 1;105(1):151-7) showed that 89 (10.4%) of 855 consecutive kidney transplant recipients tested positive for SARS-CoV-2 antibodies. Risk factors for infection included a nonwhite background, diabetes, and a history of allograft rejection. Risk factors for mortality in individuals who developed COVID-19 were older age and receiving steroids. Second Opinion: This study shows that the rate of SARS-CoV-2 infection in kidney transplant recipients is similar to the one observed in the general population in the same area (13%), indicating that transplant recipients are not at increased risk of COVID-19. However, the investigators raise the interesting point that since transplant individuals were advised to shelter earlier than the general population, they may be in fact more susceptible. This statement is hard to substantiate, but the identification of specific risk factors for infection and poor outcomes is crucial to tailor strategies to prevent spread of the infection. This is particularly important, considering that kidney transplant recipients may be at increased risk of prolonged viral spread and in-host viral mutations, making them not just a particularly fragile population for COVID-19 but also a potentially major source of further contagions.
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http://dx.doi.org/10.1159/000515165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089451PMC
May 2021

Complement in membranous nephropathy: what we thought we knew and what we really know.

Authors:
Paolo Cravedi

Kidney Int 2021 Mar 24. Epub 2021 Mar 24.

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

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http://dx.doi.org/10.1016/j.kint.2021.03.010DOI Listing
March 2021

Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study.

PLoS One 2021 24;16(3):e0248276. Epub 2021 Mar 24.

Pediatric Nephrology Unit, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, Turin, Italy.

Objectives: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed. We hypothesized that colchicine, by counteracting proinflammatory pathways implicated in the uncontrolled inflammatory response of COVID-19 patients, reduces pulmonary complications, and improves survival.

Methods: This retrospective study included 71 consecutive COVID-19 patients (hospitalized with pneumonia on CT scan or outpatients) who received colchicine and compared with 70 control patients who did not receive colchicine in two serial time periods at the same institution. We used inverse probability of treatment propensity-score weighting to examine differences in mortality, clinical improvement (using a 7-point ordinary scale), and inflammatory markers between the two groups.

Results: Amongst the 141 COVID-19 patients (118 [83.7%] hospitalized), 70 (50%) received colchicine. The 21-day crude cumulative mortality was 7.5% in the colchicine group and 28.5% in the control group (P = 0.006; adjusted hazard ratio: 0.24 [95%CI: 0.09 to 0.67]); 21-day clinical improvement occurred in 40.0% of the patients on colchicine and in 26.6% of control patients (adjusted relative improvement rate: 1.80 [95%CI: 1.00 to 3.22]). The strong association between the use of colchicine and reduced mortality was further supported by the diverging linear trends of percent daily change in lymphocyte count (P = 0.018), neutrophil-to-lymphocyte ratio (P = 0.003), and in C-reactive protein levels (P = 0.009). Colchicine was stopped because of transient side effects (diarrhea or skin rashes) in 7% of patients.

Conclusion: In this retrospective cohort study colchicine was associated with reduced mortality and accelerated recovery in COVID-19 patients. This support the rationale for current larger randomized controlled trials testing the safety/efficacy profile of colchicine in COVID-19 patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990208PMC
April 2021

Erythropoietin administration expands regulatory T cells in patients with autoimmune hepatitis.

J Autoimmun 2021 May 13;119:102629. Epub 2021 Mar 13.

Department of Internal Medicine, Northwestern University, Chicago, IL, USA; Northwestern Feinberg School of Medicine, Chicago, IL, USA; Division of Gastroenterology & Hepatology and Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA. Electronic address:

Objective: Autoimmune hepatitis (AIH) is a chronic liver disease associated with impaired regulatory T cell (Treg) number and function. Erythropoietin (EPO) is a kidney-produced erythropoietic hormone that has known immune-modulating effects, including Treg induction. Whether EPO administration increases Treg in patients with AIH is unknown.

Methods: We treated six stable AIH patients with a single 1000 IU dose of EPO and comprehensively characterized changes in Treg overall and in Treg subsets before and at 4 and 12 weeks after treatment using mass cytometry (CyTOF) combined with an unbiased clustering approach (Phenograph) based on 22 Treg-relevant cell-surface markers.

Results: EPO was well-tolerated and no patients showed significant changes in hematological parameters, liver enzymes, or IgG levels from baseline to 12 weeks following EPO administration. Total Treg and Treg/CD8 T cell ratios significantly increased at 4 weeks and returned to baseline levels at 12 weeks after EPO injection. We identified 17 Treg subsets of which CD4CD25CD127 HLADR Treg had the highest increase and the most favorable Treg/CD8 ratio upon EPO treatment. At 12 weeks after EPO administration, the HLADR Treg subset also returned to values comparable to those at baseline. Ex vivo assays documented that Treg were functional and the ones isolated at 12 weeks after EPO injection were significantly more suppressive than the ones isolated at baseline. In Treg-depleted assays, EPO did not show a significant effect on IFN-γ+, IL-2, and IL-17 CD4 T cells.

Conclusion: In stable AIH patients, EPO increases overall Treg and particularly those expressing the high function marker HLA-DR. These results provide the rationale for future studies testing the hypothesis that EPO or EPO analogues improve outcomes of AIH patients by increasing Treg.
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http://dx.doi.org/10.1016/j.jaut.2021.102629DOI Listing
May 2021

COVID-19 and the Kidney: A Worrisome Scenario of Acute and Chronic Consequences.

J Clin Med 2021 Feb 25;10(5). Epub 2021 Feb 25.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Acute kidney injury (AKI) is a common finding in patients with coronavirus disease 2019 (COVID-19) and has been associated with higher rates of death when compared to COVID-19 patients without kidney injury. Whereas the definitive pathogenesis of COVID-19-related AKI (CoV-AKI) is not clear, histopathologic evidence seems to point at multiple etiologies for the disease, including indirect and direct viral kidney injury. The high incidence of CoV-AKI, along with the aggressive clinical presentation of this entity, have increased the demands for kidney replacement therapies, rapidly overwhelming the supplies of healthcare systems even in major tertiary care centers. As a result, nephrologists have come up with alternatives to maximize the efficiency of treatments and have developed non-conventional therapeutic alternatives such as the implementation of acute peritoneal dialysis for critically ill patients. The long-term implications of CoV-AKI are yet unknown, though early studies suggest that around one third of the patients who survive will remain dependent on kidney replacement therapy. Nephrologists and healthcare workers need to be familiar with the clinical presentation and therapeutic challenges of CoV-AKI in order to develop strategies to mitigate the burden of the disease for patients, and for services providing kidney replacement therapies.
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http://dx.doi.org/10.3390/jcm10050900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956338PMC
February 2021

Hypertension and glomerular diseases: the importance of a holistic approach.

J Nephrol 2021 Feb 12. Epub 2021 Feb 12.

Centre Hospitalier Le Mans, Le Mans, France.

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http://dx.doi.org/10.1007/s40620-021-00977-4DOI Listing
February 2021

Complement, a Therapeutic Target in Diabetic Kidney Disease.

Front Med (Lausanne) 2020 21;7:599236. Epub 2021 Jan 21.

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

Currently available treatments of diabetic kidney disease (DKD) remain limited despite improved understanding of DKD pathophysiology. The complement system is a central part of innate immunity, but its dysregulated activation is detrimental and results in systemic diseases with overt inflammation. Growing evidence suggests complement activation in DKD. With existent drugs and clinical success of treating other kidney diseases, complement inhibition has emerged as a potential novel therapy to halt the progression of DKD. This article will review DKD, the complement system's role in diabetic and non-diabetic disease, and the potential benefits of complement targeting therapies especially for DKD patients.
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http://dx.doi.org/10.3389/fmed.2020.599236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858668PMC
January 2021

Preimplantation Histological Score Associates with 6-Month GFR in Recipients of Perfused, Older Kidney Grafts: Results from a Pilot Study.

Nephron 2021 22;145(2):137-149. Epub 2021 Jan 22.

Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò": Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: Biopsy-guided selection of older kidneys safely expands the organ pool, and pretransplant perfusion improves the preservation of these fragile organs. Herein, we studied morphofunctional variables associated with graft outcomes in perfused, histologically evaluated older kidneys.

Methods: This single-center prospective cohort pilot study evaluated the relationships between preimplantation histologic scores and renal perfusion parameters during hypothermic, pulsatile, machine perfusion (MP) and assessed whether these morphofunctional parameters associated with GFR (iohexol plasma clearance) at 6 months after transplantation in 20 consecutive consenting recipients of a biopsy-guided single or dual kidney transplant from >60-year-old deceased donors.

Results: The donor and recipient age was 70.4 ± 6.5 and 63.6 ± 7.9 years (p = 0.005), respectively. The kidney donor profile index (KDPI) was 93.3 ± 8.4% (>80% in 19 cases), histologic score 4.4 ± 1.4, and median (IQR) cold ischemia time 19.8 (17.8-22.8 h; >24 h in 5 cases). The 6-month GFR was 41.2 (34.9-55.7) mL/min. Vascular resistances positively correlated with global histologic score (p = 0.018) at MP start and then decreased from 0.88 ± 0.43 to 0.36 ± 0.13 mm Hg/mL/min (p < 0.001) in parallel with a three-fold renal flow increase from 24.0 ± 14.7 to 74.7 ± 31.8 mL/min (p < 0.001). Consistently, vascular resistance reductions positively correlated with global histologic score (p = 0.009, r = -0.429). Unlike KDPI or vascular resistances, histologic score was independently associated with 6-month GFR (beta standardized coefficient: -0.894, p = 0.005).

Conclusions: MP safely improves graft perfusion, particularly in kidneys with severe histologic changes that would not be considered for transplantation because of high KDPI. The preimplantation histologic score associates with the functional recovery of older kidneys even in the context of a standardized program of pulsatile perfusion.
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http://dx.doi.org/10.1159/000512341DOI Listing
January 2021

Anti-HLA and anti-SARS-CoV-2 antibodies in kidney transplant recipients with COVID-19.

Transpl Int 2021 03 26;34(3):596-599. Epub 2021 Feb 26.

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

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http://dx.doi.org/10.1111/tri.13829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013187PMC
March 2021

Immune and gene expression profiling during tacrolimus to everolimus conversion early after liver transplantation.

Hum Immunol 2021 Feb 17;82(2):81-88. Epub 2020 Nov 17.

Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States. Electronic address:

Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver transplant. Blood samples were collected at month 3 (withdrawal initiation), 4 (withdrawal completion), 4.5 and 6 (both everolimus alone). 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption. Before tacrolimus withdrawal, eventual rejecters had higher percentages of CD56 NK cells and CD19CD27CD24 memory B cells, and lower levels of T cells expressing the exhaustion marker PD-1. Over time, memory B cells, Ki-67CD3 (proliferating) cells and CD4CD127CD25 FOXP3 Tregs increased in rejecters. Tregs also increased in non-rejecters over time. The number of differentially expressed genes progressively increased in rejecters, particularly in mTOR, Eukaryotic Initiation Factor 2, and Neuroinflammation signaling pathways. There was no difference in anti-HLA antibodies between the groups. In summary, blood mononuclear cell and gene expression may predict successful vs. failed early tacrolimus withdrawal in liver transplant recipients. While needing validation, these preliminary findings highlight the potential for cellular and molecular biomarkers to guide decision-making during tacrolimus weaning.
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http://dx.doi.org/10.1016/j.humimm.2020.10.012DOI Listing
February 2021

Review: Ischemia Reperfusion Injury-A Translational Perspective in Organ Transplantation.

Int J Mol Sci 2020 Nov 13;21(22). Epub 2020 Nov 13.

Research Institute-IDIVAL, 39011 Santander, Spain.

Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.
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http://dx.doi.org/10.3390/ijms21228549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696417PMC
November 2020

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

Harnessing T cell exhaustion to improve solid organ transplant outcomes.

Am J Transplant 2021 04 6;21(4):1660-1661. Epub 2020 Nov 6.

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

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http://dx.doi.org/10.1111/ajt.16372DOI Listing
April 2021

Handling immune-suppressive therapies during SARS-CoV-2 pandemic: insights from pediatric datasets.

J Nephrol 2020 10;33(5):883-885

Division of Nephrology, Dialysis, Transplantation, IRCCS Giannini Gaslini Children's Hospital, Via Gerolamo Gaslini 5, 16148, Genova, Italy.

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http://dx.doi.org/10.1007/s40620-020-00821-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512027PMC
October 2020

Totally tubular, dude: rethinking DKD pathogenesis in the wake of SGLT2i data.

J Nephrol 2021 06;34(3):629-631

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

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http://dx.doi.org/10.1007/s40620-020-00868-0DOI Listing
June 2021

Remodeling of the Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response.

Front Immunol 2020 7;11:1748. Epub 2020 Aug 7.

Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Elderly individuals are the most susceptible to an aggressive form of coronavirus disease (COVID-19), caused by SARS-CoV-2. The remodeling of immune response that is observed among the elderly could explain, at least in part, the age gradient in lethality of COVID-19. In this review, we will discuss the phenomenon of immunosenescence, which entails changes that occur in both innate and adaptive immunity with aging. Furthermore, we will discuss inflamm-aging, a low-grade inflammatory state triggered by continuous antigenic stimulation, which may ultimately increase all-cause mortality. In general, the elderly are less capable of responding to neo-antigens, because of lower naïve T cell frequency. Furthermore, they have an expansion of memory T cells with a shrinkage of the T cell diversity repertoire. When infected by SARS-CoV-2, young people present with a milder disease as they frequently clear the virus through an efficient adaptive immune response. Indeed, antibody-secreting cells and follicular helper T cells are thought to be effectively activated in young patients that present a favorable prognosis. In contrast, the elderly are more prone to an uncontrolled activation of innate immune response that leads to cytokine release syndrome and tissue damage. The failure to trigger an effective adaptive immune response in combination with a higher pro-inflammatory tonus may explain why the elderly do not appropriately control viral replication and the potential clinical consequences triggered by a cytokine storm, endothelial injury, and disseminated organ injury. Enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe COVID-19.
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http://dx.doi.org/10.3389/fimmu.2020.01748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427491PMC
September 2020

COVID-19 and the Kidneys: An Update.

Front Med (Lausanne) 2020 21;7:423. Epub 2020 Jul 21.

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

The new coronavirus disease 2019 (COVID-19) has become a world health emergency. The disease predominantly effects individuals between 30 and 79 years of age with 81% of cases being classified as mild. Despite the majority of the general population displaying symptoms similar to the common cold, COVID-19 has also induced alveolar damage resulting in progressive respiratory failure with fatalities noted in 6.4% of cases. Direct viral injury, uncontrolled inflammation, activation of coagulation, and complement cascades are thought to participate in disease pathogenesis. Patients with COVID-19 have displayed kidney damage through acute kidney injury, mild proteinuria, hematuria, or slight elevation in creatinine possibly as consequence of kidney tropism of the virus and multiorgan failure. The impact of COVID-19 on patients with pre-existing kidney impairment, including those with chronic kidney disease, kidney transplant recipients, and individuals on hemodialysis (HD) has not yet been clearly established. No specific treatments for COVID-19 have been found yet. Research has revealed several agents that may have potential efficacy against COVID-19, and many of these molecules have demonstrated preliminary efficacy against COVID-19 and are currently being tested in clinical trials.
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http://dx.doi.org/10.3389/fmed.2020.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385132PMC
July 2020

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients.

Am J Transplant 2020 11 2;20(11):3149-3161. Epub 2020 Oct 2.

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

Whether kidney transplant recipients are capable of mounting an effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adaptive immune response despite chronic immunosuppression is unknown and has important implications for therapy. Herein, we analyzed peripheral blood cell surface and intracellular cytokine phenotyping by flow cytometry along with serum antibody testing in 18 kidney transplant recipients with active coronavirus disease 2019 (COVID-19) infection and 36 matched, transplanted controls without COVID-19. We observed significantly fewer total lymphocytes and fewer circulating memory CD4 and CD8 T cells in the COVID-19 subjects. We also showed fewer anergic and senescent CD8 T cells in COVID-19 individuals, but no differences in exhausted CD8 T cells, nor in any of these CD4 T cell subsets between groups. We also observed greater frequencies of activated B cells in the COVID-19 patients. Sixteen of 18 COVID-19 subjects tested for anti-SARS-CoV-2 serum antibodies showed positive immunoglobulin M or immunoglobulin G titers. Additional analyses showed no significant correlation among immune phenotypes and degrees of COVID-19 disease severity. Our findings indicate that immunosuppressed kidney transplant recipients admitted to the hospital with acute COVID-19 infection can mount SARS-CoV-2-reactive adaptive immune responses. The findings raise the possibility that empiric reductions in immunosuppressive therapy for all kidney transplant recipients with active COVID-19 may not be required.
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http://dx.doi.org/10.1111/ajt.16261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436882PMC
November 2020
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