1,721,148 research outputs found
mTOR-Inhibition and COVID-19 in Kidney Transplant Recipients: Focus on Pulmonary Fibrosis
Full text linkKidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities (e.g., cardiovascular disease, diabetes) and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis
Older donors and older recipients in kidney transplantation
No full textOver the last 2 decades, while kidney transplantation
became the therapy of choice for end-stage renal
disease, the increasing gap between the limited
supply of cadaveric donors and the rising demand for
kidneys led to the consideration of alternative strategies
to provide more organs for transplant. The significant
increase of mean donor age suggested the use
of kidneys from older donors. In addition, an increasing
number of donors with significant comorbidities
(e.g., hypertension and diabetes) or deceased due to
stroke have been used since the early 1990s, leading
to the definition of the fuzzy and disputed concept of
“marginal” donors. Such organs are eligible for organ
donation but, because of extreme age and other clinical
characteristics, are expected to produce allografts
at risk for diminished posttransplant function. Thus,
the challenge is now to improve the graft outcome
gap between patients receiving grafts from “marginal”
and “optimal” donors. This implies appropriate
transplantation strategies during all transplant phases,
including reduction of cold ischemia time, recipient
selection, adaptation of immunosuppressive drug
regimens, increase in nephron mass by dual kidney
transplantation and improvement in the graft selection
process using histological criteria. This review summarizes
the current definition of a marginal donor and
provides some suggestions for clinical management
of these particular kidney transplants. We believe that
in this particular transplanted population, an effective
balance should be ensured between maintaining graft
survival, reducing the impact of immunosuppressive
toxicity and maximizing patient quality of life through
the reduced incidence of cardiovascular disease and
malignancies
There is a choice for immunosuppressive drug nephrotoxingcity: Is it time to change?
No full textThe central issue in organ transplantation remains suppression
of allograft rejection. Thus, development of
immunosuppressive drugs is the key to successful allograft
function. New immunosuppressive drugs were
introduced on the basis of their ability to reduce the
incidence of acute rejection and to demonstrate shortterm
outcomes at least equivalent to those achieved
with the use of established immunosuppressive therapy.
Although short-term renal allograft survival has
improved since the introduction of calcineurin inhibitors
(CNIs), long-term renal allograft survival remains
a major concern, with chronic allograft nephropathy
(CAN) being the principal cause of renal allograft loss
after the first year. CAN has traditionally been viewed
as the result of repeated low-grade immune responses
directed against allogeneic tissue, but recent evidence
indicates that nonimmunological or alloantigen-independent
factors also contribute to its pathogenesis.
CNI nephrotoxicity occurs soon after initiation of therapy,
is more clearly dose-dependent. This scenario
presents a clear need for new strategies that produce
adequate immunosuppression to prevent acute rejection
and simultaneously reduce adverse effects associated
with CNI-related therapies. To obtain significant
long-term improvement in renal allograft outcomes, it
may be necessary to adopt new immunosuppressive
regimens that rely less on CNIs
Immunosuppressive drugs and renal transplantation
No full textAlthough the use of new immunosuppressive drugs, and their combination have drastically reduced the incidence of acute rejections, the graft survival is unchanged in the last ten years. The immunosuppressive drugs can be divided in four classes, according to their different site of molecular action: proliferative signal inhibitors, amplification signal inhibitors; STATs inhibitors, DNA synthesis inhibitors. Steroids act on immune system through several mechanisms. Azathioprine is an anti-metabolite that inhibits de-novo synthesis of purins, acting on S-phase of cellular cycle. Mycophenolate-Mofetil (MMF) is also an anti-metabolite, purine synthesis inhibitor that, differently from azathioprine, acts specifically on IMPDH (Inositolmonophosphate-dehydrogenasis) through a non-competitive mechanism. Calcineurin inhibitors (cyclosporin and tacrolimus) act on amplification of intracellular signal. The most important therapeutic side-effect of calcineurin inhibitors is the nephrotoxicity. Other inhibitor agents of the amplification signal are monoclonal antibodies anti-á chain of IL-2 (CD25). Another drug used in the last years, is sirolimus (SRL) or rapamycine, an immunosuppressive agent that act, through the inhibition of T lymphocyte activation
Kaposi's sarcoma and mTOR: a crossroad between viral infection neoangiogenesis and immunosuppression
No full textThe incidence of Kaposi’s sarcoma (KS) among the recipients of solid organ
transplants is about 500 times the rate in the general population, suggesting a
role for immunosuppression in the development of the disease. The drugs used
for the induction and maintenance of immunosuppression and the length of
treatment with these agents influence both the incidence and the type of cancer
development. The clinical presentation of KS in transplant recipients is often
limited to the skin. The risk of death from KS is related to the form and extent
of the lesions. The main approach to managing transplant-associated KS is to
reduce or even discontinue immunosuppressive therapy; this strategy carries a
risk of acute rejection of the graft. KS is a multicentric tumor composed of
endothelium-lined vascular spaces and spindle-shaped cells. Its pathogenesis is
unclear. Recent evidence suggests that vascular endothelial growth factor
(VEGF) is likely to be a growth factor for KS cells: blocking the interaction
between VEGF and Flk-1/KDR can abolish VEGF-induced growth of the
tumor. Recently, Sirolimus, a drug used in kidney-transplant recipients, has
been suggested to reduce KS progression in transplant recipients. This unexpected
effect of the drug confirms previous experimental information on KS
pathogenesis and may shed light on an array of molecular mechanisms, modulated
by Sirolimus, of potential clinical interest in the transplantation scenario
Management of side effects of sirolimus therapy
No full textSirolimus (SRL) has been shown to improve long-term graft survival in several calcineurin inhibitor avoidance/minimization protocols. Although SRL has been suggested to reduce the progression of chronic renal graft damage and to prevent the development of neoplasia, two of the most prominent challenges in the field of transplantation, its use is significantly limited by an extremely high incidence of side effects. Some of the side effects are directly linked to the antiproliferative action of SRL, whereas the mechanisms underlying most of the undesired effects of the drug are still far from being clarified. Nevertheless, there is an increasing body of evidence linking most these drug-associated events to SRL dose. In addition, it is now possible to identify well-defined risk factors for most of these effects. Thus, to limit SRL-related side effects the two golden rules are (1) accurate selection of patients to be treated and (2) avoidance of high SRL doses
Skin cancer in solid organ transplant recipients: still an open problem
No full textIn the last two decades, the optimization of organ preservation and surgical techniques, and the personalized immunosuppression have reduced the rate of acute rejections and early post-transplant complications. However, long-term graft survival rates have not improved over time, and evidence suggest a role of chronic calcineurin inhibitor toxicity in this failure. Solid organ transplant recipients may develop chronic dysfunction/damage and several comorbidities, including post-transplant malignancies. Skin cancers, mostly non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), are the most common malignancies in Caucasian solid organ transplant recipients. Several factors, together with immunosuppression, may contribute to the susceptibility for skin cancers which, although often treatable, could be associated with a much higher mortality rate than in the general population. The rapid identification and treatment (including reduction of immunosuppression and early surgical treatments) have an important role to avoid an aggressive behavior of these malignancies. Organ transplant recipients with a history of skin cancer should be followed closely for developing new and metastatic lesions. Additionally, patient education on the daily use of sun-protective measures and the recognition of the early signs (self-diagnosis) of coetaneous malignancies are useful preventive measures. Finally, clinicians should make themselves aware of the problem and build, in every clinical follow-up center, collaborative network involving transplant clinicians, dermatologists and surgeons who should work together to easily identify and rapidly treat these complications. In this review, we discuss the current literature regarding the epidemiology, risk factors, diagnosis, preventive strategies and treatments of skin cancer in organ transplantation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
mRNA as a medicine in nephrology: the future is now
No full textThe successful employment of messenger RNA (mRNA) as vaccine therapy for the prevention of COVID-19 infection has spotlighted the attention of scientific community onto the potential clinical application of these molecules as innovative and alternative therapeutic approaches in different fields of medicine. As therapy, mRNAs may be advantageous due to their unique biological properties of targeting almost any genetic component within the cell, many of which may be unreachable using other pharmacological/therapeutic approaches, and encoding any proteins and peptides without the need for their transport into the nuclei of the target cells. Additionally, these molecules may be rapidly designed/produced and clinically tested. Once the chemistry of the RNA and its delivery system are optimized, the cost of developing novel variants of these medications for new selected clinical disorders is significantly reduced. However, although potentially useful as new therapeutic weapons against several kidney diseases, the complex architecture of kidney and the inability of nanoparticles that accommodate oligonucleotides to cross the integral glomerular filtration barrier have largely decreased their potential employment in nephrology. However, in the next few years, the technical improvements in mRNA that increase translational efficiency, modulate innate and adaptive immunogenicity, and increase their delivery at the site of action will overcome these limitations. Therefore, this review has the scope of summarizing the key strengths of these RNA-based therapies and illustrating potential future directions and challenges of this promising technology for widespread therapeutic use in nephrology
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