Ageing and immunosuppression in kidney transplantation.

ABSTRACT

Modern approaches to tailor-made, individualized immunosuppressive therapy for patients receiving organ transplantation require a rethinking of therapeutic strategies when it comes to older persons receiving kidney transplants, especially from deceased older donors. This review article makes the case for the use of calcineurin-inhibitor-free immunosuppressive induction/maintenance protocols in this "worst-case scenario" and discusses the theoretical and clinical data that support this recommendation. We will discuss modern theories of ageing, emphasizing the free-radical theory in relation to new insights into the mechanisms of innate immunity. In this context, a new, modified theory of ageing is presented. Increased generation of reactive oxygen species during ageing, via increased leakage of these oxidizing molecules from mitochondria, may contribute to senescence and age-related diseases by direct damage to intracellular DNA, proteins, and lipids. In addition, free-radical-mediated tissue injury, accompanied by induction of damage-associated molecular patterns, may result in activation of both inflammatory and vascular cells of the innate immune system, contributing (via inflammatory processes) to ageing and age-related diseases such as atherosclerosis. Calcineurin-inhibiting agents have been shown to induce oxidative stress and are thus defined as "proageing" drugs. Their use in older patients may aggravate the preexisting oxidized intracellular state and therefore should be avoided. In contrast, inosine-monophosphate dehydrogenase-inhibiting agents such as mycophenolate mofetil have been shown to even ameliorate oxidative stress and are thus defined as "antiageing" drugs. Therefore, their use for immunosuppression in older patients receiving kidney transplantation is suggested. This recommendation is supported by data from a prospective trial on the application of a calcineurin inhibitor-free, mycophenolate-mofetil--based induction/ maintenance immunosuppressive protocol in older recipients of kidneys from deceased older donors the 5-year patient and 5-year allograft survival rates are currently 87% and 70%, respectively.