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Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring.
Waldman, M, Soler, MJ, García-Carro, C, Lightstone, L, Turner-Stokes, T, Griffith, M, Torras, J, Valenzuela, LM, Bestard, O, Geddes, C, et al
Kidney international. 2021;(1):227-237
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Abstract
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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Post-renal transplant malignancies: Opportunities for prevention and early screening.
Turshudzhyan, A
Cancer treatment and research communications. 2021;:100283
Abstract
GOAL OF THE REVIEW While transplant recipients are aware of increased malignancy risk, there is little consensus on the preventative measures. The goal of this review is to bring available preventative measures to light and prompt more research to be done with ultimate goal of developing an individualized prevention plan for each patient based on risk factors and available screening tools. INTRODUCTION Transplant surgery offers patients with end-stage renal disease a longer life expectancy with help of immunosuppressive therapies. Nonetheless, life-long immunosuppression comes at a cost of post-renal transplant malignancies, which have become the leading cause of morbidity in this patient group. DISCUSSION Post-renal transplant cancers can develop through either de novo, by donor-related transmission, or recurrence of recipient's pre-transplant cancer. While immunosuppressive therapy is considered to be the leading cause, weakened immunosurveillance of neoplastic cells and inadequate immune response against oncogenic viruses also plays an important role. The most common cancers seen in renal transplant patients are skin cancers and post-transplant lymphoproliferative disorder (PTLD). Risk factors for skin cancers have are ultraviolet light, human papilloma virus infection, and use of cyclosporin and azathioprine. Numerous viral infections have been associated with transplant-related malignancies post-transplant. CONCLUSION While lowering of immunosuppressive therapy remains the treatment of choice, it may lead to graft failure. Given some of the presented malignancies have modifiable risk factors and options for screening, clinical outcomes can be improved. Limiting skin exposure, dermatologic screening, and prophylactic retinoids can help lower the incidence rate of skin malignancy. Endoscopic screening for renal transplant patients can help identify gastric adenocarcinoma early and improve survival rates. Some of the post-transplant malignancies have been responsive to anti-viral treatment.
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Targeting immunometabolism as an anti-inflammatory strategy.
Pålsson-McDermott, EM, O'Neill, LAJ
Cell research. 2020;(4):300-314
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Abstract
The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
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IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome.
Trautmann, A, Vivarelli, M, Samuel, S, Gipson, D, Sinha, A, Schaefer, F, Hui, NK, Boyer, O, Saleem, MA, Feltran, L, et al
Pediatric nephrology (Berlin, Germany). 2020;(8):1529-1561
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Abstract
Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
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Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content.
Kaur, S, Srivastava, G, Sharma, AN, Jolly, RS
British journal of pharmacology. 2015;(9):2286-99
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Abstract
BACKGROUND AND PURPOSE Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action. EXPERIMENTAL APPROACH Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. KEY RESULTS CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21(CIP1/WAF1) . The effect of CaeA on cell proliferation was reversible. CONCLUSIONS AND IMPLICATIONS CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron.
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Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease.
Simmons, K, Michels, AW
Rheumatic diseases clinics of North America. 2014;(4):797-811
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Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disorder resulting from immune-mediated destruction of insulin-producing beta cells within the pancreatic islets. Prediction of T1D is now possible, as having 2 or more islet autoantibodies confers a 100% risk of diabetes development. With the ability to predict disease development, clinical trials to prevent diabetes onset have been completed and are currently under way. This review focuses on the natural history, prediction, and prevention trials in T1D. We review the lessons learned from these attempts at preventing a chronic autoimmune disease and apply the paradigm from T1D prevention to other autoimmune disorders.
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B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.
Elder, ME, Nayak, S, Collins, SW, Lawson, LA, Kelley, JS, Herzog, RW, Modica, RF, Lew, J, Lawrence, RM, Byrne, BJ
The Journal of pediatrics. 2013;(3):847-54.e1
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Abstract
OBJECTIVE To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. STUDY DESIGN Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. RESULTS Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. CONCLUSION B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.
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Efficacy, effectiveness, immunogenicity--are not the same in vaccinology.
Banaszkiewicz, A, Radzikowski, A
World journal of gastroenterology. 2013;(41):7217-8
Abstract
Manuscript of Carrera et al is devoted to immunization in inflammatory bowel disease (IBD) that is very important issue in gastroenterology. However, some specific definitions used in the article need clarification. Efficacy of vaccine is measured in a randomised, placebo-controlled studies, that are expensive and difficult to plan. Moreover, it is unethical to offer a placebo instead of vaccine. For all of these reasons, efficacy of vaccine is measured in IBD patients rarely. Effectiveness of vaccine is measured as an epidemiological affect from observational studies. These studies are also uncommon in IBD because it would be difficult to perform a study that assess the prevalence of one rare disease (vaccine-preventable) in patients with a chronic rare condition, such as IBD. Immunogenicity of vaccine refers to the ability of a vaccine to induce an immune response in a vaccinated individual that is, in fact, the matter of the article.
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Herbal medicines for immunosuppression.
Amirghofran, Z
Iranian journal of allergy, asthma, and immunology. 2012;(2):111-9
Abstract
Herbal medicines have been used for centuries to treat different illnesses. Among more than 20,000 herbal medicines available for humans, a limited number have sufficiently been studied and numerous remained to be investigated for their efficacy in treating human diseases. A number of herbal products are in use for their immunosuppressive effects. This capacity of herbs may have useful applications in immune-mediated disorders including autoimmune diseases and organ transplant rejection. Plants such as Salvia miltiorrhiza and Tripterygium wilfordii has been shown to reduce inflammatory cytokines and mediators, indicating their value in the treatment of acute graft rejections and autoimmunity. Tanacetum parthenium inhibits the release of pro-inflammatory mediators from macrophages and lymphocytes and Curcuma longa down regulates the expression of cytokines and chemokines as well as the transcription factor NF-kappaB. There has been growing interest to investigate novel anti-inflammatory or immunosuppressive activities from various sources particularly herbal medicines. This review focuses on the plants that have recently received more attention regarding their influence on the immune system, being reported as immunosuppressive and anti-inflammatory agents and promising protective effects for immune-mediated diseases.
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Impact of maintenance immunosuppressive regimens--balance between graft protective suppression of immune functions and a near physiological immune response.
Weimer, R, Deisz, S, Dietrich, H, Renner, F, Bödeker, RH, Daniel, V, Kamali-Ernst, S, Ernst, W, Padberg, W, Opelz, G
Transplant international : official journal of the European Society for Organ Transplantation. 2011;(6):596-609
Abstract
The Symphony study showed superior 1-year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin-secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post-transplant. Tacr- compared with CsA-based immunosuppression was independently associated with increased IL-2 (P<0.0001, CD4 cells; P=0.014, CD8 cells) and CD4 cell IL-4 responses (P=0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL-10 responses (P=0.008), B-cell IL-6R expression (P<0.0001) and ISC formation [P=0.020, staphylococcus cowan strain I (SAC I); P=0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL-4 by Tacr, decreased CD4 cell IL-10 responses by MMF) and suppression of B-cell functions (MMF), whereas Tacr/Aza was associated with physiological IL-2 and IL-4 and stronger humoral responses which may reduce the risk of infectious disease complications.