Tacrolimus acute nephrotoxicity

Tacrolimus acute nephrotoxicity can be manifested as asymptomatic changes in GFR, clinically significant AKl and HUS [290, 661-675]. Paradoxically, TAC has been used as an alternative treatment for patients with CSA-induced HUS [676, 677]. However, cases of HUS recurrence after conversion from CSA to TAC have... 

Tacrolimus acute nephrotoxicity can manifest itself as clinically significant acute renal failure, asymptomatic changes in glomerular filtration rate [254,527-533] or hemolytic-uremic syndrome [534-538]. Even being a cause of hemolytic-uremic syndrome, tacrolimus has been advocated as an alternative treatment for patients with CsA-induced hemolytic-uremic syndrome [539, 540]. However, cases of patients with CsA-induced hemolytic-uremic syndrome that recurred after conversion from CsA to tacrolimus have been reported, indicating that this approach is not completely safe [541]. 

Other mediators have been related to tacrolimus acute nephrotoxicity like decreased serum fibrinolytic activity [587], sympathetic overactivity [149, 588], increased renal glutathione levels [589] and increased serotonin production [552]. 

Tacrolimus nephrotoxicity has been reviewed (68) and is considered to be very similar to that described with ciclosporin. The clinical and histological characteristics of acute tacrolimus nephrotoxicity have been described from a retrospective analysis of 67 patients with renal transplants, of whom 27 developed acute nephrotoxicity, in seven of whom underljdng moderate-to-severe renal arteriosclerosis might have predisposed to tacrohmus nephrotoxicity (69). 

Shimizu T, Tanabe K, Tokumoto T, Ishikawa N, Shinmura H, Oshima T, Toma H, Yamaguchi Y. Qinical and histological analysis of acute tacrolimus (TAC) nephrotoxicity in renal allografts. Clin Transplant 1999 13(Suppl I) 48-53. 

Tacrolimus causes acute reversible renal dysfunction in renal [661-663,667], hver [290,664-666,679,680], heart [681-683] and pulmonary [684, 685] transplant recipients and in patients with immunologically mediated diseases [686]. Tacrolimus-induced GFR and RBF decrease is associated with an important increase in renal vascular resistance, both in humans and rodents [63,679,687-692]. Calcium channel blockers improved renal function in TAC-treated liver transplant recipients [693] and in animal models of TAC nephrotoxicity [689,694-6%]. Tacrohmus acute nephrotoxicity, similar to CSA, shows normal renal histology or non-specific changes such as isometric cytoplasmic vacuolation in tubular epithelial cells, microcalcification, giant mitochondria and lysosomes, and necrosis and early hyahnosis of individual smooth muscle cells in the afferent arterioles, which revert with drug reduction or discontinuation [697-699]. 

NakatanIT, Uchida J, IwalT, Matsumura K, NaganumaT, Kuratsukuri K, Suglmura K. Renin mRNA expression and renal dysfunction in tacrolimus-induced acute nephrotoxicity, int J Mol Med 2003 11 75-78. 

If taken together, those data about acute tacrohmus nephrotoxicity suggest that although the net effect of this drug on vascular reactivity, tubular cells and renal function is very similar to that caused by CsA, the mechanisms of tacrolimus-induced functional renal in-jiuy are not obligatory the same implicated in CsA-induced acute nephrotoxicity. 

Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, Gritsch A, McCauley J, Demetris AJ, Randhawa K. Clinical features of acute reveisible tacrolimus (FK506) nephrotoxicity in kidney transplant recipients. Clin Transplant ( 991) 11, 237-42. 

Amlodipine A 14-year-old renal transplant recipient developed acute nephrotoxicity with a high tacrolimus trough concentration after taking amlodipine during an acute episode of gastroenteritis Calcium chan-... 

In two women aged 37 and 69, acute and reversible tacrolimus nephrotoxicity developed after the addition of clarithromycin for an upper respiratory tract infection (76). 

Combination of sirolimus with tacrolimus virtually eliminates acute rejection. However, the adverse effects of both drugs are potentiated, increasing the nephrotoxicity of tacrolimus (11). 

Gomez G, Alvarez ML, Errasti P, Lavilla FJ, Garcia N, Ballester B, Garcia I, Purroy A. Acute tacrolimus nephrotoxicity in renal transplant patients treated with clarithromycin. Transplant Proc 1999 31(6) 2250-1. 

Clinical experience following kidney transplantation suggests that primary prophylaxis with tacrolimus results in 1-year graft and patient survival rates that are equivalent to those achieved with Cy A therapy, although with lower rates of acute rejection episodes.Five-year follow-up data suggest improved graft survival with tacrolimus compared with Cy A. Nephrotoxicity, hypertension, and posttransplant diabetes mellitus may occur and v/ere reported commonly in the early studies. ... 

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. 

Among the differential diagnoses are acute rejection, ATN, and/or cyclosporine or tacrolimus toxicity (see Chap. 46). These processes are not mutually exclusive. Definitive diagnosis is made by renal biopsy. In the presence of an elevated serum creatinine level, clinicians may reduce the dose of cyclosporine or tacrolimus to minimize the potential for drug nephrotoxicity and hasten the recovery from ATN. This practice may result in subtherapeutic immunosuppressant concentrations and hasten the occurrence of acute rejection. DGF predisposes patients to acute rejection. Induction therapy (e.g., using antibody preparations) and delaying the initiation of cyclosporine or tacrolimus administration may be useful in this setting. 

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]. ... 

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. 

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