Tacrolimus and Cyclosporine both inhibit prostaglandin production in endothelial cells. Hence, the mechanism of nephrotoxicity of calcineurin inhibitors can be considered comparable to the nephrotoxicity of NSAIDs. For some reason, my pharm course never taught us this (we still learned the immunosuppresants but not this mechanism), it was only until my Transplant rotation did an attending explain it to me.
Tacrolimus and Cyclosporine -> reduced prostaglandin production -> Afferent arteriole constriction -> reduced GFR and diminished renal blood flow -> nephrotoxicity -> chronic kidney disease
Chronic kidney disease => hypertension (kidneys unable to maintain proper fluid and electrolyte balance in the body, leading to hypertension). Also consider that if a transplanted kidney (most likely reason why somebody would be taking tacrolimus), if the donor has HTN, once that kidney is transplanted, the recipient will develop HTN (through an unknown mechanism). Chronic rejection in transplant patients is also an ongoing problem, further damaging the kidney graft, furthering the chronic kidney injury.
Chronic kidney disease -> diminished activity of 1,25-OH Vit D hydroxlyase ->low levels of active 1,25-OH Vit D -> Low serum calcium -> Secondary Hyperparathyroidism -> Elevated PTH -> Elevated osteoclast activity -> increased bone resorption ->Osteoporosis
How does Tacrolimus lead to DM? I wouldn't know. I'd imagine there might be some insulin resistance somehow induced by Tacrolimus. Although, the most common cause for renal transplantation today is DM... but I imagine that tacrolimus somehow initiates or exacerbates the risk factors of DM in patients, I just don't know how.
