Renal transplantation tacrolimus nephrotox

In 16 renal transplant patients with suspected ciclosporin nephrotoxicity, the addition of mycophenolate allowed safe reduction in the dosage of ciclosporin, with subsequent improvement in renal function and arterial blood pressure over 6 months (1). It might allow the rapid withdrawal of glucocorticoids in patients taking ciclosporin or tacrolimus, and therefore reduce the incidence of glucocorticoid-induced post-transplant diabetes, hypercholesterolemia, and hypertension (2). There have been several reports of patients with ciclosporin-associated thrombotic micro-angiopathy/hemolytic-uremic syndrome in whom mycophenolate was successfully substituted (3,4). 

Long-term follow-up (mean of 93 months) of tacroU-mus-based immunosuppression has been reported in 121 adult patients with liver transplants (10). Infections were the most common causes of deaths (17 patients out of 42), and half of them occurred during the first year after transplantation. Cardiovascular events (seven patients) or de novo malignancies (three patients) were also important causes of death. End-stage renal disease related to tacrolimus nephrotoxicity was noted in two patients who required renal transplantation At 7 years, other important adverse effects included hyperkalemia (30%) or... 

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). 

In 14 patients with renal transplants, there was a closed relation between individual tacrolimus whole blood trough concentrations and the occurrence of adverse effects (124). The incidence of tacrolimus adverse effects was 76% with tacrolimus concentrations above 30 ng/ml and only 5.3% with concentrations below 10 ng/ml. This relation was found in all separate groups of adverse effects analysed, that is nephrotoxicity, neurotoxicity, infections, and others. In contrast, there was no relation between tacrolimus concentrations and rejection episodes. Accordingly, the authors stressed that tacrolimus whole blood trough concentrations should be strictly kept under 20 ng/ml. 

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. 

Flaas M, Meehan SM, Josephson MA, Wit EJ, Woodle ES, Thistlethwaite JR. Smooth muscle-specific actin levels in the urine of renal transplant recipients correlation with cyclosporine or tacrolimus nephrotoxicity. Am J Kidney Dis 1999 34 69-84. 

Khanna AK, Pieper GM. NADPH oxidase subunits (NOX-1, p22phox, Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model. Nephrol Dial Transplant 2007 22 376-385. 

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. 

Toxicity The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperhpidemia, and gum hyperplasia. Hyperuricemia may lead to worsening of gout, increased P-glycoprotein activity, and hypercholesterolemia. Nephrotoxicity occurs in the majority of patients treated and is the major indication for cessation or modification of therapy. Hypertension occurs in -50% of renal transplant and almost all cardiac transplant patients. Combined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic, although this apparently is more problematic in patients treated with tacrohmus see below). Especially at risk are obese patients, African American or Hispanic recipients, or those with family history of type 2 diabetes or obesity. Cyclosporine, as opposed to tacrolimus, is more hkely to produce elevations in low-density lipoprotein (LDL) cholesterol. 

Higgins R, Ramaiyan K, Dasgupta T, Kanji H, Fletcher S, Lam F, Kashi H. Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than widi cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities. Nephrol Dial Transplant (2004) 444-50. 

A renal transplant recipient developed severe nephrotoxicity related to a toxic tacrolimus trough concentration associated with diarrhea and use of a calcium channel blocker. 

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-... 

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. 

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... 

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. 

Overah, the reported incidence of tacrolimus-associated nephrotoxicity varies from 18 to 42% in liver transplant patients among 128 patients who had early and late episodes of renal allograft dysfunction (1-156 weeks after transplantation) requiring biopsy, tacrohmus nephrotoxicity was estimated to account for only 17% of cases... 

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]. 

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). ... 

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