Tacrolimus chronic nephrotoxicity

Andoh et al developed an experimental model of tacrohmus-induced chronic nephrotoxicity through a salt-depletion maneuver in rats [549, 563]. A particular characteristic of this model is that renal functional changes and structural injury occur with tacrolimus blood levels equivalent to those found in tacrolimus treated patients, in a striking contrast with the CsA chronic nephrotoxicity model, where extremely high CsA blood levels are achieved. In this tacrohmus model there is an early and dose-dependent decrease in glom-... 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

Cyclosporine and tacrolimus have dramatically enhanced the success of solid organ transplantation. Nephrotoxicity, however, remains a major dose-limiting adverse effect of both drugs. " Early acute hemodynamically-mediated renal insufficiency and delayed chronic interstitial nephritis have been observed (see section on chronic interstitial nephritis later in this chapter). ... 

Since acute DIN appears to be dose related, pharmacokinetic and pharmacodynamic monitoring is an important means of preventing toxicity. However, the persistent presence of therapeutic or low cyclosporine concentrations cannot preclude nephrotoxicity. Calcium channel blockers may antagonize the vasoconstrictor effect of cyclosporine by dilating glomerular afferent arterioles and preventing acute decreases in renal blood flow and glomerular filtration. Lastly, decreased doses of cyclosporine or tacrolimus, primarily when used in combination with other non-nephrotoxic immunosuppressants, may minimize the risk of toxicity, but this may increase the risk of chronic rejection. 

The nephrotoxicity profile of tacrolimus is very similar to that of CsA. Tacrolimus induces acute and reversible functional changes in renal function, chronic renal irreversible structural injury, electrolyte disturbances, renal tubular acidosis and hemolytic-uremic syndrome. There are some few and important differences tacrolimus induces less hypertension but more glucose metabohsm impairment than CsA [242, 515-521]. Also resembling CsA, tacrolimus association with drugs that interfere with the cytochrome P-450 metabolism or with other nephrotoxic drugs, can precipitate acute renal dysfunction [522-526]. ... 

It has been shown that subjects with renal diseases such as IgA nephropathy, membranous prohferative glomerulonephritis, focal sclerosis, and lupus nephritis have levels of endothelin that are significantly higher than those in healthy subjects [209]. Increased circulating ET-1 concentrations and urinary excretion of ET-1 have been observed in patients treated with the nephrotoxic immunosuppressive agents cyclosporine A and tacrolimus (FK-506) [210]. Other nephrotoxic agents, such as cisplatin, also increase urinary excretion of ET [211]. In patients with chronic renal disease, urinary excretion of ET-1 is significantly elevated when compared to normal values (Table 10). 

Shimizu T, Ishida H, Shirakawa H, Omoto K, Tanabe K, Yamaguchi Y. Clinical and histological analysis of chronic tacrolimus nephrotoxicity in renal allografts. Transplant Proc 2008 40(7) 2370-2. 

The possibility of drug nephrotoxicity has to be excluded, either directly caused by calcineurin inhibitors (ciclosporin, tacrolimus) or more indirectly amplified by drug interactions. Again, the definitive diagnosis is provided by the biopsy, showing acute or chronic lesions associated with calcineurin-in-hibitor-induced nephrotoxicity. 

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