Tacrolimus kidney transplantation

The introduction of PP2B (calcinemin) inhibitors revolutionized kidney transplantation. Cyclosporine A and tacrolimus (FK506) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. Cyclosporine A was in use clinically long before its mechanism of action was elucidated. 

It is often difficult to differentiate ARF from acute rejection in the kidney transplant recipient, as both conditions may present with similar symptoms and physical examination findings. However, fever and graft tenderness are more likely to occur with rejection while neurotoxicity is more likely to occur with cyclosporine or tacrolimus toxicity. Kidney biopsy is often needed to confirm the diagnosis of rejection.42... 

Organ rejection prophylaxis Prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that tacrolimus be used concomitantly with adrenal corticosteroids. Because of the risk of anaphylaxis, reserve the injection for patients unable to take the capsules orally. 

Kidney transplantation The recommended starting oral dose is 0.2 mg/kg/day administered every 12 hours in 2 divided doses. The initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated, for example, by a serum creatinine of 4 mg/dL or less). Black patients may require higher doses to achieve comparable blood concentrations. 

Insulin-dependent posttransplant diabetes mellitus (PTDMj. lnsulin-dependent PTDM was reported in 20% of tacrolimus-treated kidney patients without pretransplant history of diabetes mellitus in the Phase 3 study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at 1 year and in 50% at 2 years posttransplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. 

Nephrotoxicity Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity has been noted in approximately 52% of kidney transplantation patients and in 33% to 40% of liver transplantation patients receiving the drug. 

Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005. 

Better compliance than with nystatin. Currently, the drug of choice for prophylaxis. A recent report suggested that clotrimazole troche can increase tacrolimus blood levels. (Vasquez E, Poliak R, Benedetti E. Clotrimazole increases tacrolimus blood levels a drug interaction in kidney transplant patients. Clin Transplant. 2001 15(2) 95-9.)... 

MacDonald AS. 2003. Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas and kidney transplantation. Transplant Proc. 35 2015-2085. 

Tanabe K, Tokumoto T, Ishida H, Ishikawa N, et al. 2004. Excellent outcome of ABO-incompatible living kidney transplantation under pre transplantation immunosuppression with tacrolimus, mycophenolate mofetil and steroid. Transpl Proc. 36 2175-2177. 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

Tacrolimus + sirolimus, tacrolimus + mycophenolate mofetil, and ciclosporin + sirolimus have been compared in recipients of their first kidney transplant (52). One-year patient and graft survival did not differ. Ciclosporin + sirolimus was associated with increased serum creatinine concentrations, reduced creatinine clearance, more frequent protocol discontinuation, more antihyperlipidemic drug therapy, and a higher incidence of post-transplant diabetes mellitus. 

The effect was observed in those with renal transplants (9.8% versus 2.7%) and those with other organ transplants (11.1% versus 6.2%), and among patients who were taking equal doses of concomitant medications in both treatment arms (12% versus 3%). Further factors associated with diabetes mellitus after kidney transplantation were older recipient age, a cadaveric organ, hepatitis C antibody status, an episode of rejection, and the use of tacrolimus (versus ciclosporin) cumulative glucocorticoid dose and calcineurin inhibitor trough concentration were not associated factors (1100). 

Panz VR, Bonegio R, Raal FJ, Maher H, Hsu HC, Joffe BI. Diabetogenic effect of tacrolimus in South African patients undergoing kidney transplantation. Transplantation 2002 73(4) 587-90. 

After kidney transplantation, 15 of 20 children tolerated tacrolimus after switching from ciclosporin for immunological reasons or adverse effects (609). The most frequent adverse effects were neuropsychological and behavioral symptoms in three children, ranging from anorexia nervosa-like symptoms, with weight loss, amenorrhea, depression, and school problems, to severe insomnia and in one child aggressive and anxious behavior. Only the last child was exposed to toxic tacrolimus blood concentrations. All the adverse effects were fully reversible after withdrawal. 

Tacrolimus, an immunosuppressant used to prevent rejection of liver and kidney transplants, is insoluble in water and is solubilized in Prograf to 5mg/ml with 20% Cremophor RH 60 and 80% ethanol and is administered by IV infusion after a 250-fold or a 1,000-fold dilution with saline or dextrose 5%. The dose of tacrolimus is up to 35 mg, which is 7 ml of Prograf, of which 1.4 ml is Cremophor RH60 per dose, representing the estimated maximum amount administered intravenously. 

A 47-year-old multiparous Hispanic woman received a living-unrelated kidney transplant for end-stage renal disease secondary to polycystic kidney disease. On the day of transplantation she received intravenous daclizumab 1 mg/kg plus methylprednisolone 300 mg and mycophenolate mofetil 3 g/day, and on day 3 ciclosporin emulsion 4 mg/kg/day. On day 8 she developed thrombotic microangiopathy without evidence of rejection. Ciclosporin was withdrawn. Plasmapheresis with fresh frozen plasma was started. Daclizumab on day 14 was postponed for 24 hours and plasmapheresis was stopped to avoid clearance of daclizumab. Thereafter she was given tacrolimus, without recurrence of hemolysis. 

Shield CF III, McGrath MM, Goss TF. Assessment of health-related quality of life in kidney transplant patients receiving tacrolimus (FK506)-based versus cyclosporine-based immunosuppression. FK506 Kidney Transplant Study Group. Transplantation 1997 64(12) 1738-43. 

Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, Gritsch A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients. Clin Transplant 1997 11(3) 237 2. 

Pergola PE, Kancharla A, Riley DJ. Kidney transplantation during the first trimester of pregnancy immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation 2001 71(7) 994-7. 

Christ B, Brockmeier D, Hauck EW, Friemann S. Interactions of sildenafil and tacrolimus in men with erectile dysfunction after kidney transplantation. Urology 2001 58(4) 589-93. 

Busque S, Demers P, St-Louis G, Boily JG, Tousignant J, Lemieux F, Smeesters C, Corman J, Daloze P. Conversion from Neoral (cyclosporine) to tacrolimus of kidney transplant recipients for gingival hyperplasia or hypertrichosis. Transplant Proc 1998 30(4) 1247-8. 

BQiem V, Brunkhorst R. Tacrolimus in kidney transplantation. A clinical review. Nephron 1998 79(l) 8-20. 

Villaverde V, Cantalejo M, Balsa A, Mola EM, Sanz A. Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506). Ann Rheum Dis 1999 58(10) 653-4. 

Martins L, Ventura A, Branco A, Carvalho MJ, Henriques AC, Dias L, Sarmento AM, Amil M. Cyclosporine versus tacrolimus in kidney transplantation are there differences in nephrotoxicity 1 Transplant Proc 2004 36 877-879. 

Ahsan N, Johnson C, GonwaT, Halloran P, Stegall M, Hardy M, Metzger R, Shield C, III, Rocher L, Scandling J, Sorensen J, Mulloy L, Light J, Corwin C, DanovitchG,WachsM, VanVeldhuisen P, Salm K,Tolzman D, Fitzsimmons WE. Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation results at 2 years. Transplantation 2001 72 245-250. 

Vincent F, Laskow DA, Neylan JF, Mendez R, Matas AJ. One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. Transplantation 1996 61 1576-1581. McLaughlin GE, Abitbol CL. Reversal of oliguric tacrolimus nephrotoxicity in children. Nephrol Dial Transplant 2005 20 1471-1415. 

Augustine JJ, Chang PC, KnaussTC, Aeder Ml, BodziakKA, SchulakJA, HricikDE. Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients. Transplantation 2006 81 1004-1009. 

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