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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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Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 1: Live Vaccines.
Benchimol, EI, Tse, F, Carroll, MW, deBruyn, JC, McNeil, SA, Pham-Huy, A, Seow, CH, Barrett, LL, Bessissow, T, Carman, N, et al
Gastroenterology. 2021;(2):669-680.e0
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines. METHODS Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient. CONCLUSIONS Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.
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Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.
Jones, JL, Tse, F, Carroll, MW, deBruyn, JC, McNeil, SA, Pham-Huy, A, Seow, CH, Barrett, LL, Bessissow, T, Carman, N, et al
Gastroenterology. 2021;(2):681-700
Abstract
BACKGROUND AND AIMS The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.
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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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Important considerations for drugs, nutritional, and herbal supplements in pediatric solid organ transplant recipients.
Pilch, NA, Sell, ML, McGhee, W, Venkataramanan, R
Pediatric transplantation. 2021;(1):e13881
Abstract
Pediatric transplant recipients are on multiple prescription and non-prescription drugs. Many patients also use dietary, nutritional, and herbal supplements. This manuscript researched formulations of immunosuppressive drugs currently available and presents information on generic immunosuppressive drugs, commonly used non-prescription medications, dietary supplements, and herbal supplements. Immunosuppressive drugs are available in various formulations. Not all formulations are interchangeable. A number of FDA-approved generic formulations are available commercially in the United States. Generally generic formulations produce similar blood concentration vs time profiles compared to brand name products in adults and are considered to be bioequivalent. NSAID should be avoided in transplant patients due to potential drug interactions and increased risk associated with NSAID use; and appropriate doses of acetaminophen should be used for treatment of pain. Over-the-counter medications, such as guaifenesin and dextromethorphan, antihistamine medications, including diphenhydramine, loratadine, cetirizine, and fexofenadine, can be safely used in pediatric solid organ transplant population. Many safe and effective over-the-counter options exist for stool softening and as laxative. Diarrhea can lead to an increase in calcineurin inhibitor levels. Food can alter the absorption of immunosuppressive drugs. Several herbal products can alter immune status of the patients or alter the blood concentration of immunosuppressive drugs or may produce renal or hepatic toxicities and should be avoided in pediatric transplant recipients. It is important to educate pediatric transplant recipients and their families about not only immunosuppressive drug therapy but also about non-prescription drugs, dietary, and herbal supplement use.
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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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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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The pharmaceutical management of cardiac allograft vasculopathy after heart transplantation.
Spitaleri, G, Farrero Torres, M, Sabatino, M, Potena, L
Expert opinion on pharmacotherapy. 2020;(11):1367-1376
Abstract
INTRODUCTION Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival after heart transplantation. Its peculiar pathophysiology involves multifactorial pathways including immune-mediated and metabolic risk factors, which are associated with the development of specific pathological lesions. The often diffuse and chronic nature of the disease reduces the effectiveness of revascularization procedures, and pharmacological prevention of the disease is the sole therapeutic approach with some proven efficacy. AREAS COVERED In this article, after briefly outlining the risk factors for CAV, the authors revise the potential pharmacological approaches that may reduce the burden of CAV. While several therapies have shown convincing efficacy in terms of CAV prevention diagnosed by coronary imaging, very few have been reported to improve prognosis with any meaningful level of evidence. EXPERT OPINION The authors believe that a customizable approach is necessary for clinical practice given the currently available evidence. Furthermore, it is important, in the future, to address the glaring therapeutic gap of an effective treatment against donor-specific antibodies, whose effect on endothelial injury is currently one of the major mechanisms of CAV development and for which no pharmacological treatment is currently available.
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Application of PLGA nano/microparticle delivery systems for immunomodulation and prevention of allotransplant rejection.
Keshavarz Shahbaz, S, Foroughi, F, Soltaninezhad, E, Jamialahmadi, T, Penson, PE, Sahebkar, A
Expert opinion on drug delivery. 2020;(6):767-780
Abstract
INTRODUCTION Allograft transplantation is an effective end-point therapy to replace the function of an impaired organ. The main problem associated with allotransplantation is the induction of immune responses that results in acute and chronic graft rejection. To modulate the response of the immune system, transplant recipients generally take high dose immunosuppressant drugs for life. These drugs are associated with serious side effects such as infection with opportunistic pathogens and the development of neoplasia. AREAS COVERED We reviewed the obstacles to successful transplantation and PLGA-based strategies to reduce immune-mediated allograft rejection. EXPERT OPINION Biomaterial-based approaches using micro- and nanoparticles such as poly (lactic-co-glycolic acid) (PLGA) can be used to achieve controlled release of drugs. This approach decreases the required effective dose of drugs and enables local delivery of these agents to specific tissues and cells, whilst decreasing systemic effects.
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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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Enteral immunonutrition versus enteral nutrition for patients undergoing oesophagectomy: a systematic review and meta-analysis.
Li, XK, Zhou, H, Xu, Y, Cong, ZZ, Wu, WJ, Luo, J, Jiang, ZS, Shen, Y
Interactive cardiovascular and thoracic surgery. 2020;(6):854-862
Abstract
OBJECTIVES According to retrospective studies, oesophageal carcinoma is the second deadliest gastrointestinal cancer after gastric cancer. Enteral immunonutrition (EIN) has been increasingly used to enhance host immunity and relieve the inflammatory response of patients undergoing oesophagectomy; however, conclusions across studies remain unclear. We aimed to evaluate the effect of EIN on the clinical and immunological outcomes of patients undergoing oesophagectomy. METHODS Four electronic databases (MEDLINE, Embase, Web of Science and Cochrane Library) were used to search articles in peer-reviewed, English-language journals. The mean difference, relative risk or standard mean difference with 95% confidence interval were calculated. Heterogeneity was assessed by the Cochran's Q test and I2 statistic combined with the corresponding P-value. The analysis was carried out with RevMan 5.3. RESULTS Six articles were finally included, with a total of 320 patients with oesophageal cancer. The meta-analysis results showed that EIN did not improve clinical outcomes (such as infectious complications, pneumonia, surgical site infection, anastomotic leak and postoperative hospital stay) or immune indices [referring to C-reactive protein, interleukin (IL)-6, IL-8, tumour necrosis factor-α]. Descriptive analysis suggested that EIN also increased the serum concentrations of IgG and the percentage of the B-cell fraction. Thus, its impact on IL-8 and IL-6 remains inconsistent. CONCLUSIONS The early-stage impact of EIN on immunological status in patients undergoing oesophagectomy is still unclear. According to the results of this meta-analysis, whether EIN could improve the clinical outcomes or biological status after oesophagectomy compared to standard enteral nutrition is uncertain. Since the impact of EIN is unclear, current guidelines that strongly advise the use of EIN should be changed, as the utility of EIN is very uncertain. More appropriately powered clinical studies are warranted to confirm its effectiveness.