Renal transplant patients

Hyperlipidemia is seen in up to 60% of heart, lung, and renal transplant patients and greater than 30% of liver transplant patients.64 66 As a result of elevated cholesterol levels, transplant recipients are not only at an increased risk of atherosclerotic events, but emerging evidence also shows an association between hyperlipidemia and allograft vasculopathy.66 Hyperlipidemia, along with other types of cardiovascular disease, is now one of the primary causes of morbidity and mortality in long-term transplant survivors.67... 

Tacrolimus has shown the propensity to cause less severe hyperlipidemia when compared with cyclosporine. Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to counteract this disease in transplant recipients.66 Studies demonstrate that steroid withdrawal in renal transplant patients lowered total cholesterol by 17% and LDL-C by 16% unfortunately, an 18% decrease in high-density lipoprotein (HDL) levels also was noted in these patients.66... 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions, including bone marrow suppression, and have been associated with lymphomas (in renal transplant patients) and pancreatitis. Myelosuppression resulting in leukopenia is related to a deficiency in TPMT in some patients. 

Everolimus, a derivative of sirolimus, is a novel macrocyclic immunosuppressant. Risk of acute rejection increases when the everolimus trough level falls below 3 fig/L in renal transplant patients.46... 

FIGURE 11.9 Representative mass chromatogram of everolimus (6.77 pg/L) and SDZ RAD 223-756 as internal standard (25 ug/l.) in a blood sample from a renal transplant patient. (Source From Korecka, M. et al., TherDrug Monit. 28, 487, 2006. With permission.)... 

In Phase I clinical trials with stable renal transplant patients, FTY720 led to a transient reduction in the number of circulating lymphocytes whilst being well-tolerated. Treatment was associated with a mild reduction in heart rate that was maximal 6 h after the first dose and returned to baseline with continuous treatment [52,53]. The mild effect on heart rate is believed to arise from SlPj and/or SlP3-mediated activation of G-protein-gated inwardly rectifying potassium (GIRK) channels in atrial myocytes [54-56]. 

A phase II clinical study of FTY720 in de novo renal transplant patients showed superior efficacy of FTY720 compared to mycophenolate mofetil, if combined with cyclosporine A and steroids [57], In a 1 year, multicentre,... 

Salvador M, Holzer H, de Mattos A, Solhnger H, Ams W, Oppenheimer E, Maca J, Hall M. (2004) Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4 231-236. 

Budde K, Glander P, Grohmann J, Bauer S, Hambach P, Hepburn H, Mai I, Sandau K, Fischer W, Neumayer HH. (2004) Pharmacokinetic and pharmacodynamic comparison of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) in maintenance renal transplant patients with tacrolimus as basic immunosuppression (P736). Transplantation 78 459 60. 

Calvo N, Sanchez-Fructuoso Al, Conesa J, Moreno A, Barrientos A. (2006) Renal transplant patients with gastrointestinal intolerability to mycophenolate mofetil Conversion to enteric-coated mycophenolate sodium. Transplant Proc 38 1396-2391. 

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information needed for the follow-up of the patient. Liver transplantation-excess mortality, graft loss, and hepatic artery thrombosis (HAT) The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. 

Renal transplant patients have a higher prevalence of clinically significant hyperlipidemia. Accordingly, carefully consider the risk/benefit in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus. 

Give the initial oral dose as soon as possible following renal, cardiac, or hepatic transplantation. It is recommended that mycophenolate be administered on an empty stomach. In stable renal transplant patients, mycophenolate may be administered with food if necessary. 

Renal transplantation 1 g administered orally twice a day (daily dosage of 2 g) for renal transplant patients. 

Elderly- 1 g twice a day for renal transplant patients, 1.5 g twice a day for cardiac transplant patients, and 1.5 g twice a day in hepatic transplant patients. 

Dosage adjustments - In renal transplant patients with severe chronic renal impairment (glomerular filtration rate [GFR] less than 25 mL/min per 1.73 m ) outside the immediate posttransplant period, avoid dosages of mycophenolate greater than 1 g administered twice a day. 

Renal transplant patients (twice-daily dosing) Time after transplantation ... 

Neutropenia Up to 2% of renal transplant patients, up to 3.6% of hepatic transplant patients, and up to 2.8% of cardiac transplant patients receiving mycophenolate developed severe neutropenia. Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of rejection. 

Initial - 15 mg/kg/day 4 to 12 hours prior to transplantation. There is a trend toward use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. Continue dose postoperatively for 1 to 2 weeks, then taper by 5% per week to a maintenance level of 5 to 10 mg/kg/day. Some centers successfully tapered the dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate. 

In renal transplant patients treated with Neoral or Gengraf, peak levels were 40% to 106% greater than those following Sandimmune administration. 

Elevated BUN and serum creatinine It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is indicated. These increases reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustments may be indicated. The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation. 

Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use muromonab-CD3. 

Renal allograft rejection Treatment of acute allograft rejection in renal transplant patients. 

Mild nephrotoxicity occurs in 25% of renal transplant patients, 38% of cardiac transplant patients, and 37% of liver transplant patients, generally 2-3 mo after transplantation (more severe toxicity generally occurs soon after transplantation). Hepatotoxicity occurs in 4% of renal transplant patients, 7% of cardiac transplant patients, and 4% of liver transplant patients, generally within the first mo after transplantation. Both toxicities usually respond to dosage reduction. 

Indications Treatment of acute allograft rejection in renal transplant patients and the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients... 

G. Other applications Intravenous Enbrel has been used to attenuate OKT3 (muromonab-CD3)-induced acute clinical syndrome in renal transplant patients. Early clinical trials have also revealed etanercept to be useful in the treatment of psoriatic arthritis. In a 12-week study, 87% of Enbrel-tre ted patients met the ACR criteria for 20% improvement, compared with 23% of placebo-controUed patients. 

Bauer S, Stormer E, Johne A, et al. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John s wort in renal transplant patients. Br J Clin Pharmacol 2003 55(2) 203-211. 

Mai I, Stormer E, Bauer S, Kruger H, Budde K, Roots I. Impact of St John s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant 2003 18(4) 819-822. 

Brunner LJ, Pai KS, Munar MY, Lande MB, Olyaei AJ, Mowry JA. Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients. Pediatr Transplant 2000 4(4) 313-321. 

Min DI, Ku YM, Perry PJ, et al. Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Transplantation 1996 62(1) 123-125. 

De novo transplant recipients, a loading dose of sirolimus of 3 times the maintenance dose should be given. A daily maintenance dose of 2 mg is recommended for use in renal transplant patients, with a loading dose of 6mg. 

PFA has recently undergone clinical evaluation in humans for the treatment of recurrent genital herpes, hepatitis B viral infection, and acquired immunodeficiency syndrome (AIDS), as well as cytomegalovirus (CMV) infection of bone marrow and renal transplant patients. 

The reports from initial clinical trials suggest that the level of immunosuppression achieved by belatacept is equivalent to cyclosporine in renal transplant patients with less chronic allograft nephropathy, stable kidney function and improved cardiovascular and metabolic profiles. 

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