Induction and maintenance immunosuppression in pediatric kidney transplantation-Advances and controversies.

Advances in immunosuppression have improved graft survival in pediatric kidney transplant recipients; however, treatment-related toxicities need to be balanced against the possibility of graft rejection. Several immunosuppressive agents are available for use in transplant recipients; however, the optimal combinations of agents remain unclear, resulting in variations in institutional protocols. Lymphocyte-depleting antibodies, specifically ATG, are the most common induction agent used for pediatric kidney transplantation in the US. Basiliximab may be used for induction in immunologically low-risk children; however, pediatric data are scarce. CNIs and antiproliferative agents (mostly Tac and mycophenolate in recent years) constitute the backbone of maintenance immunosuppression. Steroid-avoidance maintenance regimens remain controversial. Belatacept and mTOR inhibitors are used in children under specific circumstances such as non-adherence or CNI toxicity. This article reviews the indications, mechanism of action, efficacy, dosing, and side effect profiles of various immunosuppressive agents available for pediatric kidney transplantation.

A Comparison of Immunosuppression Regimens in Hand, Face, and Kidney Transplantation.

BACKGROUND: Authors have speculated that vascularized composite allotransplantation (VCA) recipients may require greater maintenance immunosuppression than solid organ transplant (SOT) recipients due to the higher antigenicity of skin. However, detailed comparisons of VCA and SOT immunosuppression regimens have been limited. METHODS: Hand and face VCA recipient immunosuppression data were collected through a systematic literature review. Kidney recipient data were obtained through a retrospective chart review of the authors' institution. Prednisone and mycophenolate mofetil (MMF) doses were compared between VCA and kidney recipients at predefined follow-up intervals (<1, 1-5, and >5 y). Tacrolimus target trough levels (TTTL) were compared at follow-up intervals of 1-5 and >5 y, and stratified into our institution's kidney transplant risk-based target ranges (4-6 ng/mL, 6-8 ng/mL) or higher (>8 ng/mL). RESULTS: Immunosuppression data were available for 57 VCA and 98 kidney recipients. There were no significant differences in prednisone doses between groups at all follow-up intervals. VCA recipient mean MMF dose was significantly greater at <1-y (1.71 ± 0.58 versus 1.16 ± 0.55 gm/d; P = 0.01). For VCA recipients, there was a significant difference (P = 0.02) in TTTL distribution over the three predefined therapeutic ranges (4-6 ng/mL, 6-8 ng/mL, and >8 ng/mL) between 1 and 5 y (24.0%, 20.0%, 56.0%, respectively) and >5 y (28.6%, 42.9%, 28.6%). CONCLUSIONS: At longer follow-up, VCA and kidney recipients receive comparable MMF/prednisone doses, and most VCA recipients are treated with TTTL similar to kidney recipients. Further research may improve our understanding of VCA's complex risk/benefit ratio, and enhance informed consent.

Recent advances in precision medicine for individualized immunosuppression.

PURPOSE OF REVIEW: The current tools to proactively guide and individualize immunosuppression in solid organ transplantation are limited. Despite continued improvements in posttransplant outcomes, the adverse effects of over-immunosuppression or under-immunosuppression are common. The present review is intended to highlight recent advances in individualized immunosuppression. RECENT FINDINGS: There has been a great focus on genomic information to predict drug dose requirements, specifically on single nucleotide polymorphisms of CYP3A5 and ABCB1. Furthermore, biomarker studies have developed ways to better predict clinical outcomes, such as graft rejection. SUMMARY: The integration of advanced computing tools, such as artificial neural networks and machine learning, with genome sequencing has led to intriguing findings on individual or group-specific dosing requirements. Rapid computing allows for processing of data and discovering otherwise undetected clinical patterns. Genetic polymorphisms of CYP3A5 and ABCB1 have yielded results to suggest varying dose requirements correlated with race and sex. Newly proposed biomarkers offer precise and noninvasive ways to monitor patient's status. Cell-free DNA quantitation is increasingly explored as an indicator of allograft injury and rejection, which can help avoid unneeded biopsies and more frequently monitor graft function.

Epstein-Barr virus associated CNS lymphoproliferative disorder after long-term immunosuppression.

The incidence of Epstein-Barr virus (EBV)associated lymphoproliferative disorders has increased with greater use of immunomodulatory therapies. We present a woman who developed subacute cognitive decline and unilateral weakness while taking long-term mycophenolate mofetil for granulomatosis with polyangiitis; her postmortem brain histopathology confirmed an EBV-driven lymphoproliferative disorder. Clinicians must have a high index of suspicion for EBV-driven lymphoma in people taking long-term immunosuppression who develop new neurological problems. We review the role of mycophenolate mofetil in EBV-driven lymphoproliferative disorders, and discuss checking EBV status in all patients starting immunosuppression and in older people already taking immunosuppression.

Tumor immune microenvironment and nano-immunotherapeutics in colorectal cancer.

Colorectal cancer (CRC) is predicted to be the second leading cause of cancer-related death in United States in 2019. Immunotherapies such as checkpoint inhibitors have proven efficacy in patients with high level of microsatellite instability and refractory to routine chemotherapy. Despite this, immunotherapy-based treatment is seriously limited by cancer immunogenicity which has evolved to evade immune surveillance in many circumstances. Efforts are made by researchers using nanoparticles (NPs) to override cancer-mediated immunosuppression, induce immune response against cancer cells or even generate memory immune cells for long-term disease control. These engineered NPs offer great opportunities in delivering cancer immunotherapy due to their unique properties, such as a high drug/antigen loading capacity, adjustable particle size, and versatile surface modification. In this review, we will highlight recent researches on the initiation and development of CRC, the immune microenvironment of CRC, and recent trends in engineering novel NPs-based immunotherapies in the treatment of CRC.

Correlation between MDSC and Immune Tolerance in Transplantation: Cytokines, Pathways and Cell-cell Interaction.

MDSCs play an important role in the induction of immune tolerance. Cytokines and chemokines (GM-CSF, IL-6) contributed to the expansion, accumulation of MDSCs, and MDSCs function through iNOS, arginase and PD-L1. MDSCs are recruited and regulated through JAK/STAT, mTOR and Raf/MEK/ERK signaling pathways. MDSCs' immunosuppressive functions were realized through Tregs-mediated pathways and their direct suppression of immune cells. All of the above contribute to the MDSC-related immune tolerance in transplantation. MDSCs have huge potential in prolonging graft survival and reducing rejection through different ways and many other factors worthy to be further investigated are also introduced.

Cell Therapy in Solid Organ Transplantation.

Transplantation is the only cure for end-stage organ failure. Current immunosuppressive drugs have two major limitations: 1) non antigen specificity, which increases the risk of cancer and infection diseases, and 2) chronic toxicity. Cell therapy appears to be an innovative and promising strategy to minimize the use of immunosuppression in transplantation and to improve long-term graft survival. Preclinical studies have shown efficacy and safety of using various suppressor cells, such as regulatory T cells, regulatory B cells and tolerogenic dendritic cells. Recent clinical trials using cellbased therapies in solid organ transplantation also hold out the promise of improving efficacy. In this review, we will briefly go over the rejection process, current immunosuppressive drugs, and the potential therapeutic use of regulatory cells in transplantation.

Actualización en vasculitis pulmonar / Pulmonary vasculitis: An update

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Research progress in stroke-induced immunodepression syndrome (SIDS) and stroke-associated pneumonia (SAP).

In recent years, stroke-induced immunodepression syndrome (SIDS) and the resulting stroke-associated infection (SAI) have become a focus of current research efforts. Inflammatory reactions after stroke promote tissue healing and eliminate necrotic cells, whereas excessive inflammatory reactions may cause secondary damage. Stroke-induced immunodepression not only reduces inflammatory reactions and protects brain tissues but also weakens the resistance of the human body against pathogens and leads to infection. Changes in the local and systemic immune system in stroke patients may play an important role in prognosis. Infection is a leading cause of death in patients following stroke, and an evaluation of the prognosis of stroke patients is associated closely with the presence of infectious complications. Among these complications, pneumonia is the most common type of infection observed after acute stroke, which exhibits the greatest effect on the recovery of neurological function. SIDS is closely related to stroke-associated pneumonia (SAP), and the use of immunodepression as an entry point may provide an efficacious treatment target and drug development strategy. An improved understanding of the pathophysiological mechanisms leading to SAP is essential to develop new treatment strategies for improving the outcomes of stroke patients.

Myasthenia gravis with antibodies to MuSK: an update.

Myasthenia gravis with antibodies to the muscle-specific tyrosine kinase (MuSK+ MG) is a rare disease with distinctive pathogenic mechanisms and clinical features. An acute onset and predominant bulbar muscle weakness are very common and highly suggestive of the disease. On the other hand, a more indolent course, atypical ocular presentation, and signs of cholinergic hyperactivity may complicate the diagnosis. Though MuSK+ MG is still a severe disease, over the years we have observed a steady reduction in the rate of respiratory crisis and a significant improvement in the clinical outcome, both likely related to earlier diagnosis and timely treatment. Despite the improved management, MuSK+ MG patients tend to remain dependent on long-term immunosuppressive treatment and may develop permanent disabling weakness. In uncontrolled studies, B cell depletion with rituximab proved effective in most patients with refractory disease, inducing prolonged clinical responses associated with a sustained reduction of serum antibody levels. Promising results from experimental studies and case reports suggest that both 3,4-diaminopyridine and albuterol may be effective as symptomatic agents.

Treating children with inflammatory bowel disease: Current and new perspectives.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterised by alternating periods of remission and relapse. Whilst the mechanism underlying this disease is yet to be fully understood, old and newer generation treatments can only target selected pathways of this complex inflammatory process. This narrative review aims to provide an update on the most recent advances in treatment of paediatric IBD. A MEDLINE search was conducted using "paediatric inflammatory bowel disease", "paediatric Crohn's disease", "paediatric ulcerative colitis", "treatment", "therapy", "immunosuppressant", "biologic", "monitoring" and "biomarkers" as key words. Clinical trials, systematic reviews, and meta-analyses published between 2014 and 2016 were selected. Studies referring to earlier periods were also considered in case the data was relevant to our scope. Major advances have been achieved in monitoring the individual metabolism, toxicity and response to relevant medications in IBD including thiopurines and biologics. New biologics acting on novel mechanisms such as selective interference with lymphocyte trafficking are emerging treatment options. Current research is investing in the development of reliable prognostic biomarkers, aiming to move towards personalised treatments targeted to individual patients.

Immunosuppression for kidney transplantation: Where are we now and where are we going?

Advances in immunosuppression have propelled kidney transplantation from a scientific curiosity to the optimal treatment for patients with end stage kidney disease. Declining rates of acute rejection have led to improvements in short term kidney transplant survival, culminating in incrementally better long term patient and allograft outcomes. Contextualized around established immune-suppressing drug targets, this review summarizes the history of the clinical science and highlights the pivotal trials that have led to present-day treatment standards at the level of both individual agents and multidrug regimens for kidney recipients. Finally, recently approved and emerging therapies are discussed, with an emphasis on challenges faced by clinicians managing this increasingly complex patient population.

Systemic lupus erythematosus: an update.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease predominantly affecting women of childbearing age. New classification criteria for SLE have greater sensitivity and therefore improve the diagnostic certainty for some patients, especially those who may previously have been labelled as having undifferentiated symptoms. Uncontrolled disease activity leads to irreversible end-organ damage, which in turn increases the risk of premature death; early and sustained control of disease activity can usually be achieved by conventional immunosuppressant therapy. The development of biological therapy lags behind that for other rheumatic diseases, with belimumab being the only targeted therapy approved by the Therapeutic Goods Administration. "Treat-to-target" concepts are changing trial design and clinical practice, with evidence-based definition of response criteria in the form of remission and low disease activity now on the horizon. While new therapies are awaited, research should also focus on optimising the use of current therapy and improving the quality of care of patients with SLE.

Metástasis hepática de origen colorrectal 12 años después de un trasplante hepático / Liver metastasis from colorectal cancer 12 years after liver transplantation

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Everolimus: «matando 2 pájaros de un tiro» en un trasplantado hepático con sarcoma de Kaposi / Everolimus: «Killing 2 birds with one stone» in a liver recipient with Kaposi sarcoma

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Systematic review: recurrent autoimmune liver diseases after liver transplantation.

BACKGROUND: Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent disease is frequently observed. AIMS: To describe the frequency and risk factors associated with recurrent AILD post-LT and provide recommendations to reduce the incidence of recurrence based on levels of evidence. METHODS: A systematic review was performed for full-text papers published in English-language journals, using the keywords 'autoimmune hepatitis (AIH)', 'primary biliary cholangitis and/or cirrhosis (PBC)', 'primary sclerosing cholangitis (PSC)', 'liver transplantation' and 'recurrent disease'. Management strategies to reduce recurrence after LT were classified according to grade and level of evidence. RESULTS: Survival rates post-LT are approximately 90% and 70% at 1 and 5 years and recurrent disease occurs in a range of 10-50% of patients with AILD. Recurrent AIH is associated with elevated liver enzymes and IgG before LT, lymphoplasmacytic infiltrates in the explants and lack of steroids after LT (Grade B). Tacrolimus use is associated with increased risk; use of ciclosporin and preventive ursodeoxycholic acid with reduced risk of PBC recurrence (all Grade B). Intact colon, active ulcerative colitis and early cholestasis are associated with recurrent PSC (Grade B). CONCLUSIONS: Recommendations based on grade A level of evidence are lacking. The need for further study and management includes active immunosuppression before liver transplantation and steroid use after liver transplantation in autoimmune hepatitis; selective immunosuppression with ciclosporin and preventive ursodeoxycholic acid treatment for primary biliary cholangitis; and improved control of inflammatory bowel disease or even colectomy in primary sclerosing cholangitis.

2222 kidney transplantations at the University Hospital Basel: a story of success and new challenges.

QUESTIONS UNDER STUDY: The aim was to investigate changes in kidney allograft donor/recipient characteristics and outcomes at our centre. METHODS: We retrospectively reviewed all 2222 kidney transplantations performed between 1967 and 2015. The population was divided into four eras on the basis of time intervals corresponding to major changes in immunosuppression and pretransplant risk stratification: (i.) 1967-1980 (n = 231), (ii.) 1981-1997 (n = 883), (iii.) 1998-2004 (n = 437), (iv.) 2005-2015 (n = 671). RESULTS: In deceased donor transplants, we observed a continuous increase of the median recipient (45, 51, 56 and 58 years; p <0.0001) and donor (26, 36, 49 and 54 years; p <0.0001) age. Notably, the frequency of expanded criteria donors increased dramatically (1%, 10%, 28%, 40%, p <0.0001). Graft survival at 1 year (63%, 82%, 89%, 95%), 5 years (46%, 66%, 72%, 78%) and 10 years (27%, 46%, 48%, 61%) significantly improved (p <0.0001). Patient survival also significantly improved and remained stable at a high level within the last three eras (1 year: 97%; 5 years: 87%; 10 years: 71%). Similar trends along with slightly better outcomes were noticed in living donor transplantations. In the most recent era, graft losses in elderly patients were in 81% of cases related to the patient's death, whereas in young patients 83% of graft losses were caused by transplant failure (mainly rejection). Allograft function at the time of patients' deaths would have allowed for calculated 10 additional years with an estimated glomerular filtration rate >15 ml/min. CONCLUSION: Despite increasing donor and recipient age, outcomes improved, illustrating ongoing progress in kidney transplantation. A major new challenge is to match the functional capacity of the donor organ with the anticipated lifespan of the recipient.