Cyclosporine renal 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. 

ESRD secondary to PCKD and failed previous transplant. One prior renal transplant that occurred in 1995 (received kidney from husband), which failed secondary to chronic allograft nephropathy in 2004 (presumably from multiple rejection episodes within the first few years after transplant). For the previous transplant, the patient was maintained on cyclosporine, mycophenolate, and prednisone. 

Several studies have assessed the clinical efficacy of cyclosporine versus tacrolimus. Most of the studies have shown similar longterm patient and allograft survival, whereas some renal transplant studies have demonstrated improved renal function in tacrolimus-treated patients. The most significant difference between the two agents appears to be their adverse-reaction profiles (Table 52-4). 

Azathioprine was originally approved by the FDA in 1968 as an adjunct immunosuppressant for use in renal transplant recipients. It is available in oral and IV dosage forms.11 Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids was the mainstay of immunosuppressive therapy. Over the past 10 years, the use of azathioprine has declined markedly due in large part to the success of the MPA derivatives, which are more specific inhibitors of T cell proliferation. 

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... 

A 40-year-old female post-renal transplant has developed evidence of osteoporosis, most likely due to cyclosporine. Which of the following agents might replace cyclosporine ... 

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,... 

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

Organ rejection Prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunological risk, cyclosporine should be withdrawn 2 to 4 months after transplantation and sirolimus dose should be increased to reach recommended blood concentrations. 

Organ rejection, prophylaxis Prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. 

Nephrotoxicity Nephrotoxicity has been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2 to 3 months after transplant and consisted of an arrest in the fall of the preoperative elevations of BUN and creatinine at a range of 35 to 45 mg/dL and 2 to 2.5 mg/dL, respectively. These elevations are often responsive to dosage reductions. More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Because these events are similar to rejection episodes, care must be taken to differentiate between them. This form of toxicity is usually responsive to cyclosporine dosage reduction. 

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. 

In most patients who develop CRF, renal transplantation from cadaver donors or living related donors is desirable. Post-transplant immuno-suppression with calcineurin inhibitors (e.g. cyclosporin, tacrolimus), anti-proliferative agents (e.g. azathioprine, myco-phenolate mofetil) and steroids (prednisolone), singly or in combination, are required. It has been... 

F. Role in therapy Either Simulect or Zenapax (daclizumab), which has the same mechanism of action, should be considered as add-on rejection prophylaxis (with cyclosporine and corticosteroids) in first renal transplant recipients. Although... 

Keown, P, and D. Niese, Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group. Kidney Int, 1998. 54(3) 938-44. 

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. 

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. 

Hermann M, Asberg A, Reubsaet JL, Sather S, Berg KJ, Christensen H. Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients. Int J Clin Pharmacol Ther 2002 40(10) 451-456. 

Brunner LJ, Munar MY, Vallian J, et al. Interaction between cyclosporine and grapefruit juice requires long-term ingestion in stable renal transplant recipients. Pharmacotherapy 1998 18(l) 23-29. 

Ketoconazole has been used in cardiac and renal transplant recipients to lower cyclosporine doses. 

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