Calcineurin inhibitor nephrotoxicity

Calcineurin inhibitor nephrotoxicity presents as two distinct forms of renal injury. Acute nephrotoxicity is a dose-dependent, hemodynamically mediated disorder, not accompanied by particular or permanent structural changes which is reversible with decrease or discontinuation of the offending drug. On the other hand, calcineurin inhibitor-induced chronic nephrotoxicity is an insidious lesion, characterized by an irreversible and progressive renal interstitial fibrosis, which may cause important impairment in renal function and even stage 5 chronic kidney disease. 

Nankivell BJ, Borrows RJ, Fung CL, O Connell PJ, Chapman JR, Allen RD.Calcineurin inhibitor nephrotoxicity longitudinal assessment by protocol hIstology.Transplantatlon 2004 78 557-565. 

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

The calcineurin inhibitors cyclosporine and tacrolimus block T cell activation by inhibiting the production of IL-2. They are associated with significant adverse events, such as nephrotoxicity, cardiovascular disease, posttransplant diabetes, and neurotoxicity. 

One of the major drawbacks of calcineurin inhibitors is their ability to cause acute and chronic nephrotoxicity. Acute nephrotoxicity has been correlated with high calcineurin inhibitor doses and usually is reversible. Chronic toxicity, however, typically is irreversible and is linked to chronic drug exposure. Table 52—4 expands on the more common calcineurin inhibitor-induced adverse events. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

However, it is important to note that the addition of nephrotoxic agents, such as amphotericin B, aminoglysides (e.g., gentamicin, tobramidn, or amikacin), and non-steroidal anti-inflammatory drugs (NSAIDs e.g., naproxen, ibuprofen, or ketorolac) may potentiate the nephrotoxic effects of the calcineurin inhibitors. 

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Sirolimus is a calcineurin inhibitor that acts as an immunosuppressant. It is administered systemically in the prophylaxis of organ rejection in kidney allograft recipients. It may be used in combination with ciclosporin, particularly initially. However since ciclosporin is markedly nephrotoxic, when sirolimus is used with ciclosporin, monitoring of kidney function is essential. 

Toxicities of the PSIs can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, there is interest in increased early use of PSIs since renal toxicity is less common with these agents. However, increased use in stem cell transplantation regimens as graft-versus-host disease prophylaxis, particularly when combined with tacrolimus, has revealed an increased incidence of hemolytic-uremic syndrome. 

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. 

Sirohmus is used for the prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoid. In patients at high risk for nephrotoxicity it has been combined with glucocorticoids and mycophenolate to avoid permanent renal damage (Kahan and Camardo, 2001). 

The molecular targets of rapamycin inhibitors (mTOR), siroiimus and everoiimus, have a distinct mechanism of immunosuppressive action different from the calcineurin inhibitors cyclosporine and TAC. As such, they are expected to be minimally nephrotoxic per se. 

Davies DR, Bittmann I, Pardo J. Histopathology of calcineurin inhibitor-induced nephrotoxicity. Transplantation 2000 69 SSI 1-SS13. 

Joy MS, Nickeleit V, Hogan SL, Thompson BD, Finn WF Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein. Pharmacotherapy 2005 25 779-789. 

Gallon L, Akalin E, Lynch P, Rothberg L, Parker M, SchianoT, Abecassis M, Murphy B. ACE gene D/D genotype as a risk factor for chronic nephrotoxicity from calcineurin inhibitors in liver transplant recipients.Transplantation 2006 81 463-468. 

Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation focus on improving renal function and nephrotoxicity. Clin Transplant 2008 22 1-15. 

Since light and heavy amino acids are chemically identical, the labeling process will not affect the chemical properties of the peptides and therefore differentially labeled peptides will co-elute from the HPLC column. However, these peptides are isotopically distinct from each other the peaks from light and heavy labeled peptides can be accurately distinguished and quantified by using mass spectrometry. An example of a study using SILAC includes the quantitative proteomic analysis of 495 proteins in renal cells towards the exploration of molecular mechanisms of calcineurin-inhibitors induced nephrotoxicity [82], In a second study, a... 

Induction—Administration of a highly intense level of immunosuppression in the perioperative period or use of antibody therapy to provide enough immunosuppression to delay administration of nephrotoxic calcineurin inhibitors. 

Sirolimus has been used to spare cyclosporine in the setting of cadaveric renal transplant since unlike the calcineurin inhibitors it is not vasoconstrictive and thus theoretically at least should be of benefit in ischemic reperfusion injury. The studies of Lieberthal mentioned above would lead one to a different strategy. Indeed there are now anecdotes appearing in the literature that similar to experimental animals, sirolimus potentiates ischemic injury following transplantation. There are few data with the combination of sirolimus and tacrolimus. However, limited information suggests that the pattern may be the same. Thus, it is clear that sirolimus used without a calcineurin inhibitor is safe from a nephrotoxic point of view but in combination with a calcineurin inhibitor there are either drug interactions or more fundamental cellular actions of sirolimus that may be adverse to renal tubular cells to impair recovery from ischemic insults such as hypotension and/or acute rejection episodes. 

Therapy typically involves a calcineurin inhibitor (e.g., cyclosporine or tacrolimus), glucocorticoids, and mycophenolate mofetil (a purine metabolism inhibitor see below), each directed at a discrete site in T-cell activation. Alternatively, sirolimus can be used to limit exposure to the nephrotoxic calcineurin inhibitors. Glucocorticoids, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, and various monoclonal and polyclonal antibodies are all approved for use in transplantation. 

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