Immunosuppression in Kidney Transplantation


• fluid retention; • osteopenia or osteonecrosis; •


Table 1: Common Drug Interactions with Calcineurin Inhibitors and Target of Rapamycin Inhibitors


acneform rash or ecchymosis; and • psychiatric disturbances.


Metabolic side effects include glucose intolerance and hyperlipidemia. These well-known side effects of steroids have led to interest in steroid- sparing regimens. While controversial, complete withdrawal of corticosteroids in low-risk patients has become standard practice in many transplant centers.12


Calcineurin Inhibitors


CNIs have formed the cornerstone of solid-organ transplant immunosuppressive regimens since the introduction of cyclosporine in the early 1980s. Cyclosporine is a small cyclic polypeptide of fungal origin. The other available CNI is tacrolimus, a macrolide antibiotic compound that became available in the US in the mid-1990s. Tacrolimus has emerged as the most commonly used CNI in the US. As described below, cyclosporine and tacrolimus have different side effects. Whether the two agents are comparably efficacious in preventing rejection or prolonging graft survival remains a subject of great debate.13


Calcineurin is an intracellular phosphatase that functions to dephosphorylate certain nuclear regulatory proteins, allowing them to pass through the nuclear membrane. These regulatory proteins then activate the transcription of several cytokines (IL-2, IL-4, interferon- alpha, and tumor necrosis factor-alpha) that promote T-cell activation. Cyclosporine binds to the cytoplasmic receptor, cyclophilin, while tacrolimus binds to the cytoplasmic receptor, FK-binding-protein (FKBP). Both the cyclosporine-cyclophilin and tacrolimus-FKBP compounds bind to calcineurin, preventing its normal function (see Figure 2). In so doing, the CNIs achieve selective inhibition of the immune system via blockade of T-cell activation.14,15


CNIs are metabolized by the cytochrome P450


3A4 enzyme system located in the liver and gastrointestinal tract. As many drugs can up- or downregulate the P450 enzyme system, vigilance is needed to avoid potential drug–drug interactions between CNIs and commonly prescribed medications (see Table 1).


Drugs that reliably decrease CNI concentration by inducing the P450 enzyme system include rifampin and anticonvulsants, such as barbiturates and phenytoin. If these drugs are required, the dose of CNI often needs to be increased to maintain therapeutic levels. Other drugs that decrease CNI levels less predictably include nafcillin, trimethoprim, imipenem, cephalosporins, and ciprofloxacin. St John’s wort, a herbal mood enhancer, can also induce the P450 enzyme system. Whenever any of these medications are used, CNI trough levels should be monitored closely.


Corticosteroids are also inducers of the P450 enzyme system. When steroids are tapered, CNI levels should be monitored closely to determine need for dose reduction.16,17


Drugs that increase CNI


concentration by inhibiting P450 activity include nondihydropyridine calcium-channel blockers, such as diltiazem and verapamil, the azole antifungal agents, such as ketoconazole, itraconazole, voriconazole, and fluconazole, and erythromycin and its analogs


US NEPHROLOGY


Drugs that Increase Levels Erythomycin Diltiazem Verapamil


Ketoconazole Itraconzazole Voriconazole Fluconazole Isoniazide


Oral contraceptives Amiodarone


Carvediol Ritonavir


Grapefruit juice


(except for azithromycin). Drugs such as diltiazem or ketoconazole are occasionally prescribed in conjunction with CNIs in an effort to lower the CNI dose and reduce cost. Other medications that inhibit P450 activity less predictably include isoniazide, oral contraceptives, amiodarone, and carvediol.


Some centers are now providing organ transplants to HIV-positive patients. It is therefore worth noting that protease inhibitors— particularly ritonavir—are potent inhibitors of P450 enzyme. Finally, a special dietary concern for all patients on a CNI is that grapefruit juice can result in higher drug levels from increased absorption.17


Non-P450 enzyme-related drug interactions can occur with cholestyramine and GoLYTELY®, which may interfere with the absorption of CNIs. Concomitant use of CNIs and 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors alter the pharmacokinetics of the ‘statin’ results in a longer half-life and a greater risk for rhabdomyolysis.


The CNIs have several noteworthy side effects, the most important of which is nephrotoxicity. In the short term, CNIs cause a dose-related, reversible renal vasoconstriction resulting in decreased renal blood flow. Concomitant use of other nephrotoxic agents, such as aminoglycosides and non-steroidal anti-inflammatory drugs (NSAIDs), should therefore be avoided. Cyclosporine has a greater vasoconstrictive effect than tacrolimus, which could explain its tendency for sodium retention and hypertension.18


In the long term, CNI


use may lead to interstitial fibrosis, although it remains unclear whether this is more likely with cyclosporine than with tacrolimus.19


Glomerular capillary thrombosis, progressing to graft failure and sometimes associated with full-blown hemolytic uremic syndrome has been reported with CNIs. CNIs can also induce hyperkalemia as a result of impaired aldosterone production and response. Avoidance or cautious use of potassium-sparing diuretics is therefore prudent.


CNIs can downregulate tubular transport proteins causing magnesuria and calciuria. Although both CNIs are associated with hyperuricemia, cyclosporine is more commonly associated with gout.


89


Drugs that Decrease Levels Rifampin


Barbituates Phenytoin Nafcillin


Trimethoprim Imipenem


Cephalosporins Ciprofloxacin St John’s Wort Corticosteroids


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