Rethinking chronic allograft nephropathy: the concept of accelerated senescence.
TLDR
A model in which the cumulative burden of injury and age exhausts the ability of key cells in epithelium or endothelium to repair and remodel to maintain tissue integrity is proposed, calling this exhaustion “senescence” to emphasize the importance of donor aging and the overlap of the pathologic lesions with age-related changes.Abstract:
Chronic rejection or chronic allograft nephropathy (CAN) is the major cause of failure of kidney transplants other than patient death, and has been extensively reviewed (1‐5). CAN is characterized by functional impairment with nonspecific pathology: tubular atrophy, interstitial fibrosis, and fibrous intimal thickening (FIT) in the arteries, with variable glomerular lesions. The risk of CAN correlates with the input, immune, and load stresses experienced by that kidney. Input refers to the preexisting chronic conditions in the donor (aging, hypertension) plus the acute injury related to the transplant process (brain death, donor maintenance, organ removal, preservation, implantation, reperfusion). Immune stress is due to rejection by antibody or cellular mechanisms, determined by histocompatibility, presensitization, host responsiveness, and the effectiveness of and compliance with immunosuppression. Load reflects hypertension, donor-recipient size disparity, proteinuria, hyperlipidemia, drug toxicity, and infectious agents. Load factors such as donor size and gender probably reflect differences in nephron dose and are relatively weak, suggesting that nephron number does not explain the strong effect of input and immune factors. What distinguishes the transplant from normal tissue is the level of injury. Injury depletes the finite ability of the tissue to repair, and triggers inflammation, which may further stress the parenchyma and vessels, increase immune recognition, and promote fibrosis. In this article we review the problem of human CAN and propose a model in which the cumulative burden of injury and age exhausts the ability of key cells in epithelium or endothelium to repair and remodel to maintain tissue integrity. We term this exhaustion “senescence” to emphasize the importance of donor aging and the overlap of the pathologic lesions with age-related changes, and to suggest analogy with senescent changes observed in cell culture. When the potential of a tissue to repair is exhausted, the endothelial functions decline and the epithelium atrophies; injury-induced inflammation persists, permitting transforming growth factor-b and other mediators to create fibrosis. Thus, fibrosis may be a default for the failure of normal healing. CAN can be minimized by reducing the burden of injury due to immune and nonimmune mechanisms, but grafts with age- and injury-induced changes may still be useful despite their limitations, and few should be discarded. Recent advances in the cellular basis of senescence in vitro may hold clues to the molecular events that limit the repair of key cells.read more
Citations
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DNA methylation-based biomarkers and the epigenetic clock theory of ageing
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TL;DR: Biomarkers of ageing based on DNA methylation data enable accurate age estimates for any tissue across the entire life course and link developmental and maintenance processes to biological ageing, giving rise to a unified theory of life course.
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Immunosuppressive Drugs for Kidney Transplantation
TL;DR: This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.
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Strategies to improve long-term outcomes after renal transplantation.
TL;DR: Current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus and the purine-synthesis inhibitor mycophenolate mofetil are discussed, which inhibits the proliferation of T cells and B cells.
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Identifying Specific Causes of Kidney Allograft Loss
Ziad M. El-Zoghby,Mark D. Stegall,Donna J. Lager,Walter K. Kremers,Hatem Amer,James M. Gloor,Fernando G. Cosio +6 more
TL;DR: Targets for investigation and intervention are identified that may result in improved kidney transplantation outcomes and alloinmunity remains the most common mechanism leading to failure.
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