Name one specific long-term systemic side effect commonly associated with therapeutic doses of calcineurin inhibitors like tacrolimus.

One specific long-term systemic side effect commonly associated with therapeutic doses of calcineurin inhibitors like tacrolimus is nephrotoxicity, which means damage to the kidneys. Calcineurin inhibitors are a class of immunosuppressive drugs, with tacrolimus being a widely used example, prescribed at therapeutic doses—meaning the appropriate amounts for treatment—primarily to prevent the immune system from rejecting a transplanted organ. These drugs achieve this by inhibiting calcineurin, an enzyme crucial for the activation of T-lymphocytes, which are immune cells involved in rejection. Nephrotoxicity, affecting the kidneys, is considered a systemic side effect because it impacts a vital organ system essential for the body's overall function. This kidney damage arises from multiple mechanisms. Firstly, calcineurin inhibitors cause vasoconstriction, or narrowing, of the afferent arterioles within the kidneys. These are small blood vessels that supply blood to the glomeruli, which are the tiny filtering units of the kidneys. This constriction reduces blood flow and oxygen delivery to the kidney tissue, leading to a decreased glomerular filtration rate (GFR), a key measure of kidney function. Secondly, these drugs also exert direct toxic effects on the renal tubular cells, which are the cells lining the kidney tubules responsible for reabsorbing essential substances and secreting waste. Over extended periods of treatment with these drugs, this chronic reduction in blood flow and direct cellular toxicity culminates in progressive structural damage within the kidney, specifically interstitial fibrosis, which is the scarring of the tissue between the kidney tubules, and tubular atrophy, the degeneration and shrinking of the kidney tubules. This damage can ultimately lead to chronic kidney disease, characterized by a persistent and often irreversible decline in kidney function, potentially necessitating dialysis or re-transplantation.