ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Kidney transplantation in adults: Maintenance immunosuppressive therapy

Kidney transplantation in adults: Maintenance immunosuppressive therapy
Literature review current through: May 2024.
This topic last updated: Mar 21, 2024.

INTRODUCTION — Maintenance immunosuppressive therapy is administered to almost all kidney transplant recipients to help prevent acute rejection and the loss of the kidney allograft. Although chronic baseline immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is decreased over time (as the risk of acute rejection decreases) to help lower the cumulative risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression.

The regimens and agents used for maintenance immunosuppression following kidney transplantation will be reviewed in this topic. Other aspects of immunosuppressive therapy in kidney transplant recipients, including the treatment of rejection, are presented separately:

(See "Kidney transplantation in adults: Induction immunosuppressive therapy".)

(See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)

(See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

GENERAL PRINCIPLES — Practically all kidney transplant recipients require immunosuppressive therapy to prevent rejection and loss of the allograft. Most patients undergoing kidney transplantation receive induction therapy with T cell-depleting or interleukin (IL) 2 receptor–blocking antibodies at the time of kidney transplantation (see "Kidney transplantation in adults: Induction immunosuppressive therapy"). This is followed by maintenance immunosuppression therapy, which is initiated during the hospital stay and continued for the life of the allograft.

Maintenance regimens consist of a combination of immunosuppressive agents that differ by mechanism of action (figure 1). This strategy minimizes morbidity and mortality associated with each class of agent while maximizing overall effectiveness through their different mechanisms of action. Specific regimens may vary by patient, transplant center, and geographic area. The major immunosuppressive agents that are available include the following:

Glucocorticoids (prednisone) (see 'Glucocorticoids' below)

Calcineurin inhibitors (CNIs; tacrolimus or cyclosporine) (see 'Calcineurin inhibitors' below)

Antimetabolite agents (mycophenolate mofetil [MMF], enteric-coated mycophenolate sodium [EC-MPS], azathioprine) (see 'Antimetabolites' below)

Mechanistic (mammalian) target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) (see 'mTOR inhibitors' below)

Costimulatory blockade agents (belatacept) (see 'Belatacept' below)

For most patients, the maintenance regimen consists of a CNI (usually tacrolimus), an antimetabolite (usually mycophenolate), and a glucocorticoid. (See 'Approach to maintenance therapy' below.)

Some patients may require modification of the initial maintenance regimen due to the development of posttransplant complications (eg, toxicity, allograft failure, acute rejection, infection, cancer) or other clinical events (eg, pregnancy, surgery). (See 'When and how to modify therapy' below.)

APPROACH TO MAINTENANCE THERAPY — For most kidney transplant recipients, we suggest a maintenance regimen consisting of triple immunosuppression therapy with the following agents:

A calcineurin inhibitor (CNI; usually tacrolimus) (see 'Calcineurin inhibitors' below)

An antimetabolite (usually mycophenolate) (see 'Antimetabolites' below)

A glucocorticoid (usually prednisone) (see 'Glucocorticoids' below)

Maintenance immunosuppression is continued for the life of the allograft. An exception to this approach is in recipients of human leukocyte antigen (HLA)-identical allografts from a monozygotic twin; such patients can be treated with low-dose immunosuppression for one to three months prior to discontinuation [1]. Theoretically, no immune response would be present, because the allograft and recipient are immunologically identical [1-4].

Our approach is largely consistent with the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for kidney transplantation and the consensus recommendations for use of maintenance immunosuppression in solid organ transplantation from the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation [5,6]. Evidence supporting this approach is provided by several randomized controlled trials and meta-analyses that demonstrate >90 percent allograft survival at one year and acute rejection rates of <20 percent with triple immunosuppressive therapy consisting of a CNI, an antimetabolite, and a glucocorticoid [7-10].

Alternative maintenance regimens include regimens containing a mechanistic (mammalian) target of rapamycin (mTOR) inhibitor or belatacept in combination with an antimetabolite and a glucocorticoid, regimens containing an mTOR inhibitor plus a CNI and a glucocorticoid, as well as glucocorticoid-free regimens (eg, dual therapy with a CNI plus an antimetabolite). However, we do not routinely use such regimens as initial maintenance immunosuppression for the following reasons:

Use of mTOR inhibitors is generally avoided in the early posttransplant period due to their association with delayed wound healing, wound dehiscence, lymphoceles, and prolonged graft dysfunction [6]. In addition, rates of acute rejection are higher with mTOR inhibitor-based regimens compared with CNI-based regimens [9]. However, an mTOR inhibitor can be used as an alternative agent in patients who cannot continue taking a CNI due to toxicity or who develop a new cancer after transplantation. (See 'mTOR inhibitors' below and 'Calcineurin inhibitor-related toxicity' below and 'Patients with a new cancer' below.)

Belatacept, when used as initial maintenance therapy, has been associated with higher rates of acute rejection compared with CNI-based regimens. In addition, belatacept is expensive and must be administered intravenously. However, belatacept can be used as an alternative agent in patients who cannot continue taking a CNI due to toxicity or who are nonadherent with therapy due to pill burden. A few centers have used belatacept with a time-limited course of tacrolimus as part of an initial maintenance regimen to avoid long-term use of CNIs and their associated adverse effects [11,12]; however, more data are needed. (See 'Belatacept' below and 'Calcineurin inhibitor-related toxicity' below and 'Patients with nonadherence to therapy' below.)

While most (approximately two-thirds) kidney transplant recipients are maintained on long-term glucocorticoids [13], some centers use glucocorticoid-free regimens in patients at low to moderate immunologic risk [5,6]. In such patients, glucocorticoids are administered at the time of transplantation but are typically discontinued within the first few days after transplant. This is based upon the desire to minimize long-term glucocorticoid exposure, thereby decreasing the risk of adverse effects with this agent. While studies comparing early glucocorticoid withdrawal (also called glucocorticoid avoidance) with glucocorticoid continuation after kidney transplantation have shown similar long-term patient and allograft survival [14,15], rates of biopsy-proven acute rejection are higher with early glucocorticoid withdrawal [15]. Thus, we, and most centers, continue low-dose glucocorticoid therapy in all patients, regardless of the risk for acute rejection or the potential adverse effects of long-term glucocorticoid exposure. (See 'Glucocorticoids' below.)

AGENTS USED FOR MAINTENANCE THERAPY

Glucocorticoids — Glucocorticoids are nonspecific antiinflammatory agents that interrupt multiple steps in immune activation, including antigen presentation, cytokine production, and lymphocyte proliferation.

Dosing – Glucocorticoid regimens vary among transplant centers, and there is no consensus on the optimal dose or maintenance schedule following kidney transplantation [5]. In the absence of acute rejection, there is little utility in maintaining patients on large doses of glucocorticoids or in tapering glucocorticoids over prolonged periods of time. Most centers attempt to taper glucocorticoids to approximately 0.05 to 0.1 mg/kg/day of prednisone (or even less) by the first few months after transplantation. At our center, patients receive intravenous methylprednisolone at the time of transplantation, followed by a rapid taper of oral prednisone to a dose of 5 mg/day by one month following kidney transplantation (table 1). Overall, the benefit of maintenance low-dose glucocorticoids at the doses utilized may include improved immunosuppression, modulation of calcineurin inhibitor (CNI) nephrotoxicity, reduced risk of cytopenias, and/or ability to avoid CNI use.

Duration – The use of long-term glucocorticoids as part of a maintenance immunosuppressive regimen varies among transplant centers. We, and most centers, continue maintenance glucocorticoids indefinitely in kidney transplant recipients, based upon data demonstrating that continuing glucocorticoid therapy reduces the risk of acute rejection and chronic allograft nephropathy compared with glucocorticoid withdrawal [15-17]. Some centers may choose to use long-term glucocorticoids in patients who are receiving a second transplant, who have a high panel of reactive antibody (PRA), or who have an immunologic cause for chronic kidney disease requiring glucocorticoids. Alternatively, some centers may choose to withdraw glucocorticoids early after transplant (within weeks to months) in patients at low to moderate risk for rejection to minimize toxicity and decrease overall immunosuppression. Long-term patient and allograft survival with this approach have been shown to be similar to that with glucocorticoid continuation [14,17]. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Assessment of immunologic risk'.)

It is less clear whether late glucocorticoid withdrawal (greater than one year posttransplant) should or should not be performed. Late withdrawal has been successfully performed in some centers, but its effect upon long-term allograft function and the risk of chronic rejection has not been conclusively evaluated [18,19].

Several randomized trials have compared outcomes with glucocorticoid continuation and glucocorticoid withdrawal/avoidance [14-17,20,21]. As examples:

A systematic review of 48 randomized trials (7803 patients) comparing glucocorticoid avoidance or withdrawal with glucocorticoid maintenance, or comparing glucocorticoid avoidance with glucocorticoid withdrawal, found no significant difference in patient mortality or allograft loss at one year posttransplant among adults [15]. However, the risk of acute rejection at one year was higher in patients treated with glucocorticoids for fewer than 14 days after transplantation (relative risk [RR] 1.58, 95% CI 1.08-2.30) and in those who were withdrawn from glucocorticoids at a later time point after transplantation (RR 1.77, 95% CI 1.20-2.61). Continuation of glucocorticoids was not associated with a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients.

In a randomized trial in 295 kidney transplant recipients that compared two immunosuppression minimization strategies (early glucocorticoid withdrawal from day 3 or reduced tacrolimus exposure [ie, target trough level of 3 to 5 ng/mL] from six months after transplant) with standard immunosuppression with basiliximab, tacrolimus, mycophenolate, and low-dose glucocorticoids, allograft function at 24 months was comparable between the treatment groups [16]. Patients in the early glucocorticoid withdrawal group had a higher frequency of treated rejection compared with those in the tacrolimus minimization and standard immunosuppression groups (24 versus 11 and 14 percent, respectively).

Longer-term outcomes were reported in a randomized trial that compared very early glucocorticoid withdrawal with low-dose, long-term glucocorticoid therapy in 386 low- to moderate-risk kidney transplant recipients [14,17]. All patients received induction therapy with either rabbit antithymocyte globulin (rATG)-Thymoglobulin (68 percent) or interleukin (IL) 2 receptor antibody (32 percent); maintenance therapy consisted of tacrolimus, mycophenolate mofetil (MMF), and seven days of glucocorticoids followed by either glucocorticoid withdrawal or continuation (taper to 5 mg/day of prednisone by six months after transplant). At five years, there was no significant difference in the primary composite of death, allograft loss, or moderate/severe rejection between the groups. The early withdrawal group had a higher incidence of chronic allograft nephropathy (10 versus 4 percent) and biopsy-proven acute rejection (18 versus 11 percent). There were no significant differences in blood pressure, posttransplant diabetes mellitus (PTDM), serum cholesterol or low-density lipoprotein levels, or rates of bone fracture or cataracts. At a median of 15.8 years after transplant, the risks of all-cause and death-censored allograft failure were similar between the treatment groups [17].

Adverse effects – Systemic glucocorticoids have adverse effects on many organ systems, including, but not limited to, hyperglycemia, fluid retention, hypertension, poor wound healing, osteoporosis, cataracts, and susceptibility to infection (table 2). These are discussed in more detail elsewhere. (See "Major adverse effects of systemic glucocorticoids".)

Calcineurin inhibitors — CNIs (tacrolimus and cyclosporine) are a cornerstone of immunosuppression in kidney and other solid organ transplantation. CNIs selectively inhibit calcineurin, thereby impairing the transcription of IL-2 and several other cytokines in T cells (figure 1). By inhibiting cytokine gene transcription, CNIs suppress T cell and T cell-dependent B cell activation. Either tacrolimus or cyclosporine is used in over 90 percent of kidney transplant recipients in the United States, with tacrolimus being much more commonly used. (See "Pharmacology of calcineurin inhibitors".)

For most patients undergoing kidney transplantation, we suggest tacrolimus rather than cyclosporine as the CNI of their maintenance immunosuppression regimen. Among kidney transplant recipients, tacrolimus is more effective than nonmodified and modified cyclosporine at lowering the rate of acute rejection [8,9,22-28]. Overall, allograft and patient survival rates are similar with the two agents [10,22-24,26,27,29-31], although some studies have shown superior allograft survival with tacrolimus [8,9].

In a meta-analysis of 30 trials (4102 patients) comparing tacrolimus and cyclosporine (nonmodified and modified), tacrolimus lowered the risk of allograft loss at six months (RR 0.56, 95% CI 0.36-0.86) [8]. The benefit from tacrolimus was diminished when used at higher doses, possibly due to increased rates of CNI toxicity and infection. Allograft loss at later time points also favored tacrolimus (RR 0.77 [95% CI 0.58-1.02] at one year, 0.74 [95% CI 0.46-1.21] at two years, and 0.71 [95% CI 0.52-0.96] at three years). In addition, tacrolimus decreased the risk of acute rejection at one year (RR 0.66, 95% CI 0.6-0.79).

In the Efficacy Limiting Toxicity Elimination (ELITE)-Symphony trial, low-dose tacrolimus, mycophenolate, and glucocorticoids (with daclizumab induction) produced higher 12-month allograft survival versus standard-dose and low-dose cyclosporine-based regimens and a low-dose sirolimus-based regimen (94 versus 93, 89, and 89 percent, respectively), although the difference with the low-dose cyclosporine regimen was not statistically significant [9]. Rates of biopsy-proven acute rejection were lower among patients receiving low-dose tacrolimus than in those receiving standard or low-dose cyclosporine or low-dose sirolimus (12 versus 26, 24, and 37 percent, respectively). However, higher rates of PTDM occurred in patients receiving low-dose tacrolimus (8 percent) versus those receiving standard-dose cyclosporine (6 percent) or low-dose cyclosporine (4 percent), and low-dose sirolimus (7 percent).

Tacrolimus — Most patients undergoing kidney transplantation receive tacrolimus as part of their maintenance immunosuppression regimen [5]. Tacrolimus is associated with lower acute rejection rates and similar overall costs compared with cyclosporine [8,29]. In addition, despite higher rates of PTDM, tacrolimus is better tolerated and preferred by patients compared with cyclosporine. Tacrolimus, unlike cyclosporine, does not lower mycophenolate levels, and therefore, relatively lower doses of mycophenolate are needed when tacrolimus is used.

Formulations Tacrolimus is available in oral, sublingual, and intravenous formulations. The available oral formulations include immediate-release capsules and two extended-release oral formulations (capsules [Astagraf XL, Advagraf] and tablets [Envarsus]) designed for once-daily administration. The efficacy and safety of immediate-release and extended-release tacrolimus formulations are comparable [32-37]. However, there are important pharmacokinetic differences between these formulations, particularly between extended-release tacrolimus tablets (Envarsus) and both immediate-release and extended-release capsules (Astagraf XL, Advagraf). Extended-release tacrolimus tablets (Envarsus) have a higher drug exposure per milligram basis, lower peak concentrations, and a longer time to maximum concentration than immediate-release tacrolimus and extended-release tacrolimus capsules (Astagraf XL, Advagraf) [38]. Thus, a 20 to 30 percent dose reduction is recommended when converting from immediate-release and extended-release capsules (Astagraf XL, Advagraf) to extended-release tablets (Envarsus) (table 1). Adverse effects of extended-release tacrolimus appear to be similar to those of immediate-release tacrolimus, with the exception of fewer tremors [35]. (See "Pharmacology of calcineurin inhibitors", section on 'Tacrolimus'.)

Dosing – Initial dosing of tacrolimus may vary from center to center. Suggested dosing and dose conversions for tacrolimus is provided in the table (table 1). (See "Pharmacology of calcineurin inhibitors", section on 'Dose' and "Pharmacology of calcineurin inhibitors", section on 'Administration'.)

Adverse effects – The adverse effects of tacrolimus and cyclosporine are generally similar and include nephrotoxicity, hypertension, neurotoxicity, electrolyte abnormalities (hyperkalemia, hypomagnesemia), metabolic abnormalities (hyperlipidemia, PTDM), infections, and an increased risk of malignancy. These are discussed in more detail elsewhere. (See "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)

Compared with cyclosporine, tacrolimus is associated with more frequent neurologic side effects (such as tremor and headache), gastrointestinal side effects (diarrhea, dyspepsia, and vomiting), and alopecia, and a higher incidence of PTDM. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus", section on 'Modifiable risk factors'.)

Cyclosporine — Cyclosporine is an alternative CNI for patients who have or who are predisposed to tacrolimus-associated toxicity.

FormulationsCyclosporine is available in nonmodified and modified formulations. Modified cyclosporine is an oral preparation of cyclosporine that involves a unique microemulsion formulation. The microemulsion is miscible in water and has improved pharmacokinetic bioavailability and less intra- and interindividual variability when compared with the standard nonmodified oral preparation [39-44]. We and most centers administer modified cyclosporine because of equivalent efficacy and more convenient administration and monitoring compared with nonmodified cyclosporine [45-47]. (See "Pharmacology of calcineurin inhibitors", section on 'Cyclosporine'.)

Dosing – Initial dosing of cyclosporine may vary from center to center. Suggested dosing for cyclosporine is provided in the table (table 1). (See "Pharmacology of calcineurin inhibitors", section on 'Dose' and "Pharmacology of calcineurin inhibitors", section on 'Administration'.)

Adverse effects – The adverse effects of tacrolimus and cyclosporine are generally similar and include nephrotoxicity, hypertension, neurotoxicity, electrolyte abnormalities (hyperkalemia, hypomagnesemia), metabolic abnormalities (hyperlipidemia, PTDM), infections, and an increased risk of malignancy. These are discussed in more detail elsewhere. (See "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)

Compared with tacrolimus, cyclosporine is associated with more frequent hirsutism, gingival hyperplasia, and hypertension.

Antimetabolites — Antimetabolite agents interfere with the synthesis of nucleic acids and inhibit the proliferation of both T and B lymphocytes (figure 1). MMF or enteric-coated mycophenolate sodium (EC-MPS) is the antimetabolite agent used in more than 90 percent of kidney transplant recipients in the United States; azathioprine is rarely used [48]. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

For most kidney transplant recipients, we suggest mycophenolate (MMF or EC-MPS) rather than azathioprine as the antimetabolite of their maintenance immunosuppression. The preference for mycophenolate as an antimetabolite is based upon multiple large trials and meta-analyses showing lower acute rejection rates, and possibly improved graft survival, with MMF as compared with azathioprine [49-60]. The best data come from a 2015 systematic review of 23 trials (3301 kidney transplant recipients) that compared the efficacy and safety of MMF versus azathioprine [49]. Compared with azathioprine, MMF reduced the risk of death-censored graft loss (RR 0.78, 95% CI 0.62-0.99), acute rejection (RR 0.65, 95% CI 0.57-0.73), and chronic allograft nephropathy (RR 0.69, 95% CI 0.48-0.99). There were no significant differences in all-cause mortality. Although there was no difference in cytomegalovirus (CMV) viremia or CMV syndrome, the risk of tissue-invasive CMV disease was higher with MMF (RR 1.7, 95% CI 1.1-2.6). Gastrointestinal symptoms (eg, diarrhea) were more common with MMF, whereas thrombocytopenia and elevated liver enzymes were more common with azathioprine. Nearly all of these studies compared azathioprine with MMF when used in combination with cyclosporine (mostly nonmodified). This may not necessarily be relevant to the combination of MMF plus tacrolimus, which is the most common combination of an antimetabolite plus a CNI.

Mycophenolate — Most patients undergoing kidney transplantation receive mycophenolate (MMF or EC-MPS) as the antimetabolite of their maintenance immunosuppression [5]. Despite its increased cost, mycophenolate is preferred over azathioprine because of its superior ability to prevent acute rejection and better side effect profile [49]. However, mycophenolate should not be used in female transplant recipients of childbearing age unless they are on long-acting contraception, have undergone surgical sterilization procedures, or have absolute infertility. Mycophenolate is teratogenic, and its use is contraindicated in pregnancy. Thus, in these patients, we prefer to use azathioprine, which does not seem to have a detrimental effect on fertility or pregnancy [61]. (See 'Pregnancy and lactation' below.)

Formulations – Oral mycophenolate is available in two different formulations: MMF and EC-MPS. MMF and EC-MPS are similar in efficacy and safety [62-67]. We prefer EC-MPS over MMF because EC-MPS may be associated with fewer gastrointestinal side effects among certain groups of patients (eg, patients with indigestion, diabetes, those treated with glucocorticoids, or patients converted from MMF to EC-MPS between 6 to 12 months posttransplant) [67,68]. If patients tolerate neither MMF nor EC-MPS, we switch to azathioprine. (See 'Azathioprine' below.)

Dosing – Suggested dosing for MMF and EC-MPS is provided in the table (table 1).

In the patient with marked gastrointestinal side effects with MMF, we first switch to EC-MPS from MMF at a molecularly equivalent dose (250 mg of MMF is equivalent to 180 mg of EC-MPS). If that is ineffective, we lower the dose of EC-MPS further or consider switching to azathioprine.

Adverse effects – The most common adverse effects of MMF and EC-MPS include bone marrow suppression and gastrointestinal disturbances (eg, persistent diarrhea, nausea, abdominal cramping). These symptoms are generally dose-related and improve with temporary or permanent dose reduction. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)

Azathioprine — Azathioprine can be used for patients who do not tolerate mycophenolate and for female patients who are pregnant or may become pregnant (ie, those without effective long-acting contraception, surgical sterilization, or infertility). (See 'Pregnancy and lactation' below.)

Dosing – Suggested dosing for azathioprine is provided in the table (table 1).

Adverse effects – Leukopenia is the most serious side effect of azathioprine. The immunosuppressive effect of azathioprine is not related to the reduction in white blood cell count; as a result, it is not necessary to increase the dose to achieve leukopenia. Azathioprine should be temporarily withheld, not just dose-reduced, if the white cell count falls below 3000/mm3 or if the count drops by 50 percent between blood draws. Recovery usually occurs within one to two weeks. The drug can then be restarted at a lower dose and increased gradually to the usual maintenance dose while monitoring the white cell count. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

The toxicity of azathioprine is primarily related to the activity of the enzyme thiopurine methyltransferase (TPMT), and deficiency of this enzyme has been associated with significant bone marrow suppression. We do not routinely test for TPMT deficiency before beginning azathioprine but perform testing in patients who develop severe myelosuppression while taking azathioprine. If the patient is found to have TPMT deficiency, we discontinue azathioprine. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)

mTOR inhibitors — Mechanistic (mammalian) target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) are structurally similar to CNIs but exert their immunosuppressive effects through calcineurin-independent mechanisms. They bind to the FK-binding protein and block the activity of a cytoplasmic protein kinase called mTOR, thereby interrupting DNA and protein synthesis and proliferation of T, natural killer, and B cells (figure 1). mTOR inhibitors are generally used as alternative agents in patients who cannot continue taking a CNI due to toxicity, who develop a new cancer after transplantation, or who are nonadherent with therapy. (See 'Calcineurin inhibitor-related toxicity' below and "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors".)

Dosing – Suggested dosing for sirolimus and everolimus is provided in the table (table 1).

Adverse effects Sirolimus and everolimus are associated with several possible adverse effects including bone marrow suppression, dyslipidemia, poor wound healing, painful mouth ulcers, peripheral edema, and, among kidney transplant recipients, an increased risk of posttransplant mortality [69-71]. These are discussed in more detail elsewhere. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Adverse effects'.)

Efficacy – The efficacy and safety of mTOR inhibitors in kidney transplant recipients have been evaluated in multiple trials and systematic reviews [72-80]. Most of these studies have examined the use of mTOR inhibitors as a replacement for either CNIs or antimetabolite agents or in combination with CNIs. Overall, none of these trials have shown any improvement in patient or allograft survival with regimens that included mTOR inhibitors, while retrospective studies of large databases have found inferior long-term allograft survival with sirolimus [72-74,80]. In addition, one meta-analysis found that sirolimus-based immunosuppression was associated with a decreased risk of malignancy but an increased risk of posttransplant mortality when compared with CNI-based strategies. The best evidence comes from the following three systematic reviews:

A systematic review of 33 randomized trials examined the use of mTOR inhibitors (sirolimus or everolimus) as a replacement for either CNIs or antimetabolic agents or in combination with CNIs [75,81]. There was no significant difference in allograft or patient survival with any comparison. Compared with patients who received a CNI, those who received an mTOR inhibitor had better kidney function for up to two years posttransplant but also had an increased risk of bone marrow suppression, dyslipidemia (RR 1.8, 95% CI 1.1-3.0), and lymphoceles (RR 3.1, 95% CI, 1.6-5.9).

Conversion from a CNI to an mTOR inhibitor among kidney transplant recipients was evaluated in a systematic review of 29 randomized trials [76]. Patients who were converted from a CNI to an mTOR inhibitor within one year posttransplant had a higher glomerular filtration rate (GFR) at one year compared with those who remained on a CNI. However, there was no difference in graft survival, and patients who switched to an mTOR inhibitor had a higher risk of acute rejection up to one year posttransplant (RR 1.72, 95% CI 1.34-2.22) as well as a higher risk of dyslipidemia and infection.

Another systematic review and meta-analysis of 21 randomized trials examined the risk of malignancy and death among 5876 kidney and kidney-pancreas transplant recipients who received immunosuppressive regimens either with or without sirolimus [77]. Compared with controls, sirolimus was associated with a decreased risk of malignancy (adjusted hazard ratio [aHR] 0.60, 95% CI 0.39-0.93) but an increased risk of death (aHR 1.43, 95% CI 1.21-1.71). The increased mortality was driven by increased cardiovascular and infection-related deaths in the sirolimus group.

Belatacept — Belatacept is a fusion protein composed of the Fc fragment of human immunoglobulin G1 linked to the extracellular domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) that selectively inhibits T cell activation through costimulatory blockade (figure 1). Belatacept is administered intravenously. Its use is generally reserved for patients who cannot continue taking a CNI due to toxicity or who are nonadherent to therapy due to pill burden [6]. A few centers have used belatacept with a time-limited course of tacrolimus as part of an initial maintenance regimen to avoid long-term use of CNIs and their associated adverse effects [11,12]; however, more data are needed.

Belatacept should not be administered to patients who are Epstein-Barr virus (EBV)-seronegative and who received a transplant from an EBV-seropositive donor or to recipients with unknown EBV status because of the risk of EBV-associated posttransplant lymphoproliferative disorder (PTLD).

Dosing – Dosing for belatacept (when converting from a CNI) is provided in the table (table 1).

Adverse effects Belatacept is associated with an increased risk of EBV-associated PTLD. Other common adverse effects include edema, hypertension, headache, diarrhea, constipation, anemia, and cough.

Efficacy – Evidence evaluating the use of belatacept in kidney transplant recipients can be divided into studies examining use of belatacept as initial maintenance immunosuppression (de novo use) and those examining conversion from a CNI-based regimen to a belatacept-based regimen.

De novo use – Multiple studies have evaluated the efficacy and safety of belatacept as part of an initial maintenance immunosuppressive regimen in kidney transplant recipients [82-94]. As examples:

-Two large trials have compared de novo belatacept with cyclosporine-based triple immunosuppression. In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT), 666 recipients of a living or standard-criteria deceased donor kidney transplant were randomly assigned to more intensive belatacept, less intensive belatacept, or cyclosporine, in conjunction with MMF and prednisone; all patients received basiliximab as induction therapy [83,91]. At 12 months, patients receiving belatacept had a higher incidence and grade of acute rejection (22 and 17 versus 7 percent in the more intensive belatacept, less intensive belatacept, and cyclosporine arms, respectively) but had better allograft function, a benefit that was sustained at seven years posttransplant (estimated GFR of 70 and 72 versus 45 mL/min/1.73 m2, respectively). In addition, rates of death or allograft loss were significantly lower at seven years in patients assigned to belatacept (12.7 and 12.8 versus 21.7 percent). PTLD was more common with belatacept, particularly among EBV-seronegative patients.

The BENEFIT-EXT trial compared the efficacy and safety of belatacept with that of cyclosporine in expanded criteria donor kidney transplant recipients, using the same study design as the one used in BENEFIT [84,95]. At 12 months, acute rejection rates were similar between groups. Similar to BENEFIT, patients treated with belatacept had better kidney function at one and seven years compared with those treated with cyclosporine. Rates of PTLD were also higher among patients treated with belatacept.

-Two trials have compared belatacept with a more contemporary tacrolimus-based regimen. One small trial comparing belatacept with a tacrolimus-based, glucocorticoid-containing regimen (all patients received MMF and prednisolone as well as basiliximab for induction) found a higher incidence of acute rejection at one year posttransplant among patients receiving belatacept (55 versus 10 percent) and no different in allograft function between the two groups [96]. Allograft loss, due to rejection, occurred in three patients, all in the belatacept group.

In a larger trial that compared belatacept with a tacrolimus-based, glucocorticoid-avoiding regimen, 316 kidney transplant recipients were randomly assigned to belatacept with alemtuzumab induction, belatacept with rATG-Thymoglobulin induction, or tacrolimus with rATG-Thymoglobulin induction; all patients received mycophenolate (MMF or EC-MPS) and a five-day glucocorticoid taper [94,97]. At two years posttransplant, patient and graft survival rates were similar among the groups. However, rates of biopsy-proven acute rejection were higher in the belatacept treatment groups than in the tacrolimus group (19 and 25 versus 7 percent).

-A retrospective single-center analysis compared outcomes among 535 kidney transplant recipients treated with belatacept and a historical cohort of 205 recipients receiving a tacrolimus-based regimen; all patients also received MMF and glucocorticoids and induction therapy with basiliximab [12]. Rates of biopsy-proven acute rejection at one year were higher among patients receiving belatacept (51 versus 21 percent). The addition of a nine-month course of low-dose tacrolimus to belatacept decreased the incidence of acute rejection to 16 percent, a rate similar to that observed in the tacrolimus group. Patient and allograft survival at four years were similar between the groups.

Conversion to belatacept – Data on the efficacy and safety of switching from a CNI-based regimen to belatacept come from two randomized trials and observational studies [92,98-103]:

-In one randomized trial in 446 kidney transplant recipients who were 6 to 60 months posttransplant and had stable allograft function on CNI-based immunosuppression, 24-month patient and graft survival were similar between patients assigned to switch to belatacept and those who were assigned to continue CNI treatment (98 and 97 percent, respectively) [102]. The belatacept conversion group had higher rates of biopsy-proven acute rejection (8 versus 4 percent) but lower rates of de novo donor-specific antibody formation (1 versus 7 percent). Estimated GFR at 24 months was higher with belatacept (55 versus 48 mL/min/1.73 m2). Serious adverse events and infections were similar between the groups; one patient in the belatacept group developed PTLD.

-Similar findings were reported in another randomized trial in 173 stable kidney transplant recipients who were 6 to 36 months posttransplant on a CNI-based regimen [92,98]. Compared with patients who continued CNI treatment, those who switched to belatacept had better allograft function at 12 and 36 months but also higher rates of acute rejection. While overall rates of serious adverse events were similar between the groups, more viral and fungal infections occurred in the belatacept group.

-Long-term outcomes after conversion to belatacept were reported in an observational study that compared 243 patients converted to belatacept with 243 matched controls who were maintained on CNIs [103]. At seven years, conversion to belatacept was associated with better allograft survival (78 percent versus 63 percent in the CNI control group). Rates of death, active antibody-mediated rejection, T cell-mediated rejection, major adverse cardiovascular events, and cancer were similar between the groups.

A higher rate of opportunistic infections (particularly CMV disease and Pneumocystis pneumonia) with belatacept conversion has also been reported in observational studies [99-101].

DRUG MONITORING — Kidney transplant recipients routinely undergo drug monitoring to achieve proper dosing and to avoid over-immunosuppression and drug toxicity. The frequency of monitoring varies depending upon the time posttransplant and transplant center protocol.

Monitoring and target levels for tacrolimus, cyclosporine, sirolimus, and everolimus are presented in the table (table 3). (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)

For patients on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), monitoring of drug levels is not generally performed. Measuring trough levels of mycophenolic acid (the active metabolite of MMF) has not been shown to correlate well with drug exposure [104,105]. Area under the curve of mycophenolic acid is considered the standard for monitoring mycophenolic acid levels, but technical challenges (eg, the need for multiple blood samples at different time points) limit its use in clinical practice.

DRUG INTERACTIONS — Several agents used for maintenance immunosuppressive therapy have drug interactions that may necessitate dose adjustments (table 4 and table 5 and table 6). A discussion of some of the more commonly encountered drug interactions seen in transplant patients is presented below. For additional information on drug interactions, refer to the drug interactions program provided by UpToDate.

Calcineurin inhibitors – Calcineurin inhibitors (CNIs; tacrolimus and cyclosporine) are substrates of cytochrome P450 CYP3A drug metabolism and P-glycoprotein (P-gp) transport. Thus, any drug that affects CYP3A4 metabolism or P-gp transport can potentially interact with CNIs and thereby cause either overdosing, with deterioration of kidney function, or underdosing, with an increased risk of rejection (table 4 and table 5 and table 6). (See "Pharmacology of calcineurin inhibitors", section on 'Food and drug interactions'.)

Common medications that increase blood levels of tacrolimus and cyclosporine include:

Calcium channel blockers – verapamil, diltiazem, nicardipine, and amlodipine

Antifungal agents – ketoconazole, itraconazole, and fluconazole

Antibiotics – erythromycin and clarithromycin

Antiviral agents – ritonavir and ritonavir-containing coformulations

Grapefruit juice

Common medications that decrease blood levels (by inducing hepatic metabolism) include:

Anticonvulsants – phenobarbital, phenytoin, and carbamazepine

Antimicrobials – rifampin and nafcillin

Other nephrotoxins may worsen the kidney toxicity of tacrolimus and cyclosporine, such as nonsteroidal antiinflammatory drugs (NSAIDs), aminoglycosides, and amphotericin B. In addition, hydroxymethylglutaryl coenzyme A reductase inhibitors (such as lovastatin) can cause rhabdomyolysis and, rarely, acute kidney injury, when given with cyclosporine.

MycophenolateMycophenolate mofetil (MMF) is metabolized by cytochrome P450 CYP3A4/5 and probably by cytochrome P450 CYP2C8. Common drug interactions with mycophenolate in transplant recipients include the following:

Coadministration of proton pump inhibitors (eg, pantoprazole, lansoprazole) and MMF may result in lower mycophenolic acid exposure, which could increase the risk of acute rejection [106-112]. However, other studies have not supported these findings [113-115]. Enteric-coated mycophenolate sodium (EC-MPS) appears less likely to interact.

Patients should avoid taking aluminum or magnesium hydroxide antacids at the same time as MMF or EC-MPS since these drugs decrease the area under the curve of mycophenolic acid by approximately 17 percent. Patients who are on sevelamer should take this medication two hours after MMF or EC-MPS since sevelamer can decrease the exposure and maximum concentration of mycophenolic acid.

Trough levels of mycophenolate appear to be lowered by the concurrent administration of cyclosporine [116-118], an effect that is not observed with tacrolimus. Tacrolimus inhibits UDP-glucuronosyltransferase, the enzyme that metabolizes mycophenolic acid (the active metabolite of MMF and EC-MPS), thereby increasing concentrations of mycophenolic acid. If tacrolimus is substituted for cyclosporine in a patient concurrently taking mycophenolate, we frequently decrease the dose of mycophenolate by 50 percent. Although the use of tacrolimus compared with cyclosporine increases MMF exposure by 20 to 30 percent, we believe that a 50 percent reduction is appropriate since, compared with a 25 percent reduction, it may be associated with fewer gastrointestinal side effects and anemia, and it may also limit the costs of an enhanced pill burden. EC-MPS at a dose of 360 mg two times per day in a patient receiving tacrolimus is generally equivalent to 720 mg two times per day in a patient receiving cyclosporine. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Drug interactions'.)

Azathioprine – Severe leukopenia can occur if xanthine oxidase inhibitors such as allopurinol or febuxostat (used for the treatment of hyperuricemia and gout) are given with azathioprine. Allopurinol and febuxostat inhibit the activity of xanthine oxidase, which also plays a role in the metabolism of azathioprine. Thus, allopurinol and febuxostat should generally be avoided in patients treated with azathioprine. If, however, the patient has severe gout and either allopurinol or febuxostat must be used, we reduce the azathioprine dose (by at least 50 percent) and carefully monitor the white blood cell count. Even with this approach, however, azathioprine may need to be discontinued. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Drug interactions'.)

mTOR inhibitors Sirolimus and everolimus are substrates of cytochrome P450 CYP3A drug metabolism. Thus, coadministration of these agents with cytochrome P450 3A inducers (such as some anticonvulsants, rifampin, St. John's wort) and with cytochrome P450 3A inhibitors (such as azole antifungals, nondihydropyridine calcium channel blockers, some macrolide antibiotics, grapefruit) can result in significant interactions (table 4 and table 5 and table 6). (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Drug interactions'.)

WHEN AND HOW TO MODIFY THERAPY — In most kidney transplant recipients, a stable maintenance immunosuppression regimen is established within the first three months after transplantation. After three months, we do not routinely reduce maintenance immunosuppression, even among stable patients. Some centers may continue to reduce maintenance immunosuppression at six months and up to one year posttransplant. Complete withdrawal of all maintenance therapy is not recommended (except in recipients of human leukocyte antigen [HLA]-identical allografts from a monozygotic twin), since it frequently leads to late acute rejection or accelerated chronic rejection. These complications most often occur in patients who are not adherent to therapy or who cannot afford to pay for the medications. (See 'Patients with nonadherence to therapy' below.)

However, some patients may require a modification of the initial maintenance immunosuppression regimen due to the development of posttransplant complications (eg, toxicity, allograft failure, acute rejection, infection, cancer) or other clinical events (eg, pregnancy, surgery). A discussion of these special patient populations is presented below.

Calcineurin inhibitor-related toxicity — Although calcineurin inhibitors (CNIs) are a fundamental component of maintenance immunosuppression in kidney transplantation, some patients are unable to tolerate these agents due to nephrotoxicity or other adverse effects. Alternative immunosuppression regimens involving the use of mechanistic (mammalian) target of rapamycin (mTOR) inhibitors or belatacept, a costimulatory blockade agent, have been designed to try to reduce toxicity while maintaining effective immunosuppression in these patients.

In patients with CNI-related toxicity, our approach is as follows:

In patients who have biopsy-proven CNI nephrotoxicity (without acute rejection), we typically discontinue the CNI and switch to either an mTOR inhibitor (sirolimus or everolimus) or belatacept. (See 'mTOR inhibitors' above and 'Belatacept' above.)

In patients who develop other serious adverse effects (eg, neurotoxicity, thrombotic microangiopathy) that can be attributed to CNIs, we first reduce the dose of the CNI by 25 to 50 percent. If the adverse effects persist in spite of dose reduction, we discontinue the CNI and switch to either an mTOR inhibitor (sirolimus or everolimus) or belatacept. (See 'mTOR inhibitors' above and 'Belatacept' above.)

The decision to use an mTOR inhibitor or belatacept depends upon multiple factors and must be made on an individual patient basis. Adverse drug reactions, drug interactions, efficacy, convenience, and cost must all be considered. Treatment with belatacept, for example, requires intravenous access, close proximity to an infusion center, and the ability to pay for this high-cost medication. In addition, belatacept may increase the risk of posttransplant lymphoproliferative disorder. Thus, we only use belatacept in Epstein-Barr virus (EBV)-seropositive patients. We generally avoid mTOR inhibitors in patients who have preexisting precautions or contraindications to these medications.

Pregnancy and lactation — Mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), and mTOR inhibitors (sirolimus and everolimus) should be avoided during pregnancy and in patients who may become pregnant. Azathioprine has been used safely in pregnant transplant patients. Cyclosporine, tacrolimus, and prednisone also appear to be safe. Pharmacokinetic factors, such as volume of distribution and metabolism, are altered with pregnancy, and drug levels require more frequent monitoring and adjustment. These issues are discussed in more detail elsewhere. (See "Sexual and reproductive health after kidney transplantation", section on 'Management of immunosuppression' and "Sexual and reproductive health after kidney transplantation", section on 'Breastfeeding'.)

Patients unable to take oral medications — Patients who are unable to take oral medications can be treated with intravenous formulations. Intravenous formulations are available for methylprednisolone, cyclosporine, tacrolimus, MMF, azathioprine, and belatacept. Patients who are taking EC-MPS can be switched to intravenous MMF. There are no intravenous formulations for sirolimus or everolimus. Suggested conversion from oral to intravenous formulations is detailed in the table (table 1). Patients should be transitioned back to oral therapy as soon as tolerated.

Some centers prefer to use sublingual rather than intravenous tacrolimus when patients are nil per os (eg, in the postoperative setting). One study found that a slightly higher dose of oral tacrolimus may be needed when converting from sublingual to oral tacrolimus [119]. Suggested conversion from oral to sublingual tacrolimus is detailed in the table (table 1).

Patients with acute rejection — An important issue is the optimal immunosuppressive strategy among patients with acute rejection. Among such patients who are being administered triple immunosuppressive therapy, we switch to mycophenolate (if they are on azathioprine) or tacrolimus (if they are on cyclosporine). Patients who develop acute rejection while on triple therapy with tacrolimus, mycophenolate, and prednisone should continue these agents at higher doses if possible. We typically start by targeting higher levels of tacrolimus (ie, 5 to 7 ng/mL). Patients who are receiving dual therapy (CNI and antimetabolite without prednisone) at the time of rejection should be initiated on long-term prednisone at 5 mg once daily.

Patients with recurrent rejection may be nonadherent to their maintenance immunosuppression, and factors contributing to poor adherence should be assessed. (See 'Patients with nonadherence to therapy' below.)

The treatment of patients with acute T cell-mediated (cellular) rejection and antibody-mediated rejection is discussed separately. (See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection" and "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

Patients who develop infection — The protocol for adjusting the immunosuppressive regimen among patients who develop infection varies among institutions but generally depends upon the severity of infection. Our approach is as follows:

In patients with life-threatening infections or evidence of sepsis, we withhold all immunosuppressive agents, except for low-dose glucocorticoids. Alternatively, some centers may hold the antimetabolite and lower the dose of the CNI rather than stopping both agents. We usually restart the CNI within one week from the time it was withheld but discontinue the antimetabolite indefinitely. If there is concern for adrenal insufficiency from long-term glucocorticoid use, we administer stress-dose glucocorticoids. The use of stress-dose glucocorticoids in patients with adrenal insufficiency is discussed separately. (See "Treatment of adrenal insufficiency in adults", section on 'Acute illness'.)

In patients with moderate infection (ie, who require admission and intravenous antibiotics but are not septic), we withhold one agent (typically the antimetabolite, such as mycophenolate or azathioprine). We usually hold this agent for four to six weeks and restart it at 50 percent of the dose that was administered prior to the infection. In patients with recurrent infection, we discontinue the antimetabolite indefinitely. Some clinicians do not alter the immunosuppressive regimen among patients with moderately severe bacterial infection but decrease the glucocorticoid dose among patients with moderately severe fungal infections.

In otherwise stable patients who develop community-acquired infections (eg, bronchitis, pneumonia, cystitis, cellulitis), we generally do not modify the maintenance immunosuppression regimen.

The adjustment of immunosuppression among patients with coronavirus disease 2019 (COVID-19), cytomegalovirus (CMV), or BK polyomavirus infection is discussed elsewhere.

COVID-19 (see "COVID-19: Issues related to solid organ transplantation", section on 'Adjusting immunosuppression')

CMV (see "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Reduction of immunosuppression')

BK polyomavirus (see "Kidney transplantation in adults: BK polyomavirus-associated nephropathy", section on 'Reduction of immunosuppression')

Patients with a new cancer — In kidney transplant recipients who develop a new cancer after transplantation, we typically reduce maintenance immunosuppression, which may result in regression of some types of tumors. The modification of maintenance immunosuppression in patients who develop a posttransplant malignancy is discussed elsewhere. (See "Malignancy after solid organ transplantation", section on 'Reduction in immunosuppression' and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Patients undergoing nontransplant surgery — Most kidney transplant recipients who undergo elective surgery do not require modification of their maintenance immunosuppressive therapy. As an exception, patients who are taking an mTOR inhibitor are at increased risk for delayed wound healing, and therefore, we typically hold the mTOR inhibitor for one week prior to surgery and switch to tacrolimus. When the surgical incision has healed, we discontinue tacrolimus and restart the mTOR inhibitor. In patients at high risk for rejection, it may be reasonable to overlap use of tacrolimus and sirolimus until a therapeutic sirolimus level is achieved. If a kidney transplant recipient undergoing elective surgery is unable to take oral medications in the perioperative setting, we typically convert the immunosuppressive agents to the intravenous formulation until the patient is able to resume taking oral medications. (See "Pharmacology of calcineurin inhibitors", section on 'Switching formulations'.)

Patients with a failing allograft — In general, maintenance immunosuppression should be reduced in a patient with a failing allograft. The modification of immunosuppression in patients with a failing allograft is discussed separately. (See "Kidney transplantation in adults: Management of the patient with a failed kidney transplant", section on 'Management of immunosuppression'.)

Patients with nonadherence to therapy — Nonadherence is a risk factor for rejection and allograft loss [69-71]. Thus, every effort should be made to identify nonadherent patients early and provide them with appropriate counseling and assistance. In patients who are known to be nonadherent with therapy, modification of the maintenance immunosuppression regimen to simplify dosing or reduce pill burden may improve adherence. As an example, sirolimus has a long half-life that permits convenient once-daily dosing. Belatacept is another option with its less frequent (monthly) administration. Alternatively, a regimen of extended-release tacrolimus, azathioprine, and prednisone provides three immunosuppressive medications with once-daily dosing. Deciding upon an alternative regimen must be made on an individual patient basis, considering factors such as adverse drug reactions, drug interactions, efficacy, convenience, and cost.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

General principles – Practically all kidney transplant recipients require immunosuppressive therapy to prevent rejection and loss of the allograft (figure 1). Most patients receive induction therapy at the time of transplantation, followed by maintenance immunosuppression, which is initiated during the hospital stay and continued for the life of the allograft. (See 'General principles' above.)

Approach to maintenance therapy – For most kidney transplant recipients, we suggest a maintenance regimen consisting of triple immunosuppression therapy with a calcineurin inhibitor (CNI), an antimetabolite, and prednisone, rather than alternative regimens (Grade 2C). We aim for the following regimen (see 'Approach to maintenance therapy' above):

Calcineurin inhibitor – For most kidney transplant recipients, we suggest tacrolimus rather than cyclosporine as the CNI of their maintenance immunosuppression regimen (Grade 2C). Tacrolimus is associated with lower acute rejection rates and is generally better tolerated than cyclosporine. (See 'Calcineurin inhibitors' above.)

Antimetabolite – For most kidney transplant recipients, we suggest mycophenolate (mycophenolate mofetil [MMF] or enteric-coated mycophenolate sodium [EC-MPS]) rather than azathioprine as the antimetabolite of their maintenance immunosuppression regimen (Grade 2C). Mycophenolate is preferred over azathioprine because of its superior ability to prevent acute rejection and its better side effect profile. However, mycophenolate is teratogenic, and we do not use mycophenolate in female recipients of childbearing age unless they are on long-acting contraception, have undergone surgical sterilization procedures, or have absolute infertility. In these patients, we prefer to use azathioprine. (See 'Antimetabolites' above.)

Glucocorticoids – Glucocorticoid regimens vary among transplant centers, and there is no consensus on the optimal dose or maintenance schedule following kidney transplantation. At our center, patients receive intravenous methylprednisolone at the time of transplantation, followed by a rapid taper of oral prednisone to a dose of 5 mg/day by one month after transplant. For most kidney transplant recipients, we suggest continuing maintenance glucocorticoids indefinitely (Grade 2C). Some centers may choose to use long-term glucocorticoids in patients that are receiving a second transplant, who have a high panel of reactive antibody (PRA), or who have an immunologic cause for chronic kidney disease requiring glucocorticoids. Alternatively, some centers may choose to withdraw glucocorticoids in patients at low to moderate risk for rejection to minimize toxicity and decrease overall immunosuppression. (See 'Glucocorticoids' above.)

Suggested dosing of these agents is presented in the table (table 1).

We do not routinely use a mechanistic (mammalian) target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or belatacept as part of an initial maintenance immunosuppression regimen. However, such agents may be used as an alternative in patients who cannot continue taking a CNI due to toxicity, who develop a new cancer after transplantation, or who are nonadherent with therapy. (See 'mTOR inhibitors' above and 'Belatacept' above.)

Drug monitoring and interactions – Kidney transplant recipients routinely undergo drug monitoring to achieve proper dosing and to avoid over-immunosuppression and drug toxicity. Monitoring and target levels for specific agents are presented in the table (table 3). Several agents used for maintenance immunosuppressive therapy have drug interactions that may necessitate dose adjustments (table 4 and table 5 and table 6). (See 'Drug monitoring' above and 'Drug interactions' above.)

When and how to modify therapy – In most kidney transplant recipients, a stable maintenance regimen is established within the first three months after transplantation. After three months, we do not routinely reduce maintenance immunosuppression, even among stable patients. Complete withdrawal of all maintenance therapy is not recommended (except in recipients of human leukocyte antigen [HLA]-identical allografts from a monozygotic twin), since it frequently leads to late acute rejection or accelerated chronic rejection. Some patients may require a modification of the initial maintenance immunosuppression regimen due to the development of posttransplant complications (eg, toxicity, allograft failure, acute rejection, infection, cancer) or other clinical events (eg, pregnancy, surgery). (See 'When and how to modify therapy' above.)

  1. Krishnan N, Buchanan PM, Dzebisashvili N, et al. Monozygotic transplantation: concerns and opportunities. Am J Transplant 2008; 8:2343.
  2. Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in identical twins. 1955. J Am Soc Nephrol 2001; 12:201.
  3. Weil R 3rd, Starzl TE, Porter KA, et al. Renal isotransplantation without immunosuppression. Ann Surg 1980; 192:108.
  4. Gumprich M, Woeste G, Kohlhaw K, et al. Living related kidney transplantation between identical twins. Transplant Proc 2002; 34:2205.
  5. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
  6. Nelson J, Alvey N, Bowman L, et al. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy 2022; 42:599.
  7. Lebranchu Y, Bridoux F, Büchler M, et al. Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy. Am J Transplant 2002; 2:48.
  8. Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005; 331:810.
  9. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357:2562.
  10. Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69:834.
  11. Johnson AC, Zhang J, Karadkhele G, et al. Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation. Am J Transplant 2024; 24:260.
  12. Adams AB, Goldstein J, Garrett C, et al. Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long-Term Renal Allograft Function. Am J Transplant 2017; 17:2922.
  13. Hart A, Lentine KL, Smith JM, et al. OPTN/SRTR 2019 Annual Data Report: Kidney. Am J Transplant 2021; 21 Suppl 2:21.
  14. Woodle ES, Gill JS, Clark S, et al. Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients: Long-term Outcomes of a Randomized Clinical Trial. JAMA Surg 2021; 156:307.
  15. Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2016; 2016:CD005632.
  16. van den Born JC, Meziyerh S, Vart P, et al. Comparison of 2 Immunosuppression Minimization Strategies in Kidney Transplantation: The ALLEGRO Trial. Transplantation 2024; 108:556.
  17. Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248:564.
  18. Arnol M, de Mattos AM, Chung JS, et al. Late steroid withdrawal and cardiovascular events in kidney transplant recipients. Transplantation 2008; 86:1844.
  19. Hollander AA, Hene RJ, Hermans J, et al. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997; 8:294.
  20. Bae S, McAdams-DeMarco MA, Massie AB, et al. Panel-reactive Antibody and the Association of Early Steroid Withdrawal With Kidney Transplant Outcomes. Transplantation 2022; 106:648.
  21. Ekberg J, Baid-Agrawal S, Jespersen B, et al. A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients. Kidney Int Rep 2022; 7:259.
  22. Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 1999; 318:1104.
  23. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64:436.
  24. Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63:977.
  25. Gonwa T, Johnson C, Ahsan N, et al. Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years. Transplantation 2003; 75:2048.
  26. Krämer BK, Montagnino G, Del Castillo D, et al. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant 2005; 20:968.
  27. Margreiter R, European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet 2002; 359:741.
  28. Azarfar A, Ravanshad Y, Mehrad-Majd H, et al. Comparison of tacrolimus and cyclosporine for immunosuppression after renal transplantation: An updated systematic review and meta-analysis. Saudi J Kidney Dis Transpl 2018; 29:1376.
  29. Hardinger KL, Bohl DL, Schnitzler MA, et al. A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients. Transplantation 2005; 80:41.
  30. Woodward RS, Kutinova A, Schnitzler MA, Brennan DC. Renal graft survival and calcineurin inhibitor. Transplantation 2005; 80:629.
  31. Irish W, Sherrill B, Brennan DC, et al. Three-year posttransplant graft survival in renal-transplant patients with graft function at 6 months receiving tacrolimus or cyclosporine microemulsion within a triple-drug regimen. Transplantation 2003; 76:1686.
  32. Silva HT Jr, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007; 7:595.
  33. Krämer BK, Charpentier B, Bäckman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010; 10:2632.
  34. Budde K, Bunnapradist S, Grinyo JM, et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. Am J Transplant 2014; 14:2796.
  35. Langone A, Steinberg SM, Gedaly R, et al. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant 2015; 29:796.
  36. Gaber AO, Alloway RR, Bodziak K, et al. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation 2013; 96:191.
  37. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant 2013; 13:760.
  38. Tremblay S, Nigro V, Weinberg J, et al. A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study. Am J Transplant 2017; 17:432.
  39. Kovarik JM, Mueller EA, Richard F, et al. Evidence for earlier stabilization of cyclosporine pharmacokinetics in de novo renal transplant patients receiving a microemulsion formulation. Transplantation 1996; 62:759.
  40. Mueller EA, Kovarik JM, van Bree JB, et al. Pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine in renal allograft recipients--a concentration-controlled comparison with the commercial formulation. Transplantation 1994; 57:1178.
  41. Kovarik JM, Mueller EA, van Bree JB, et al. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 1994; 83:444.
  42. Mueller EA, Kovarik JM, van Bree JB, et al. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm Res 1994; 11:301.
  43. Kovarik JM, Mueller EA, van Bree JB, et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation--a multicenter investigation in kidney transplant patients. Transplantation 1994; 58:658.
  44. Wahlberg J, Wilczek HE, Fauchald P, et al. Consistent absorption of cyclosporine from a microemulsion formulation assessed in stable renal transplant recipients over a one-year study period. Transplantation 1995; 60:648.
  45. Keown P, Landsberg D, Halloran P, et al. A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group. Transplantation 1996; 62:1744.
  46. Frei UA, Neumayer HH, Buchholz B, et al. Randomized, double-blind, one-year study of the safety and tolerability of cyclosporine microemulsion compared with conventional cyclosporine in renal transplant patients. International Sandimmun Neoral Study Group. Transplantation 1998; 65:1455.
  47. Pescovitz MD, Barone G, Choc MG Jr, et al. Safety and tolerability of cyclosporine microemulsion versus cyclosporine: two-year data in primary renal allograft recipients: a report of the Neoral Study Group. Transplantation 1997; 63:778.
  48. Lentine KL, Smith JM, Miller JM, et al. OPTN/SRTR 2021 Annual Data Report: Kidney. Am J Transplant 2023; 23:S21.
  49. Wagner M, Earley AK, Webster AC, et al. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2015; :CD007746.
  50. Mycophenolate mofetil in cadaveric renal transplantation. US Renal Transplant Mycophenolate Mofetil Study Group. Am J Kidney Dis 1999; 34:296.
  51. Neylan JF. Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1997; 64:1277.
  52. Lang P, Pardon A, Audard V. Long-term benefit of mycophenolate mofetil in renal transplantation. Transplantation 2005; 79:S47.
  53. Remuzzi G, Cravedi P, Costantini M, et al. Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial. J Am Soc Nephrol 2007; 18:1973.
  54. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60:225.
  55. Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al. Long-term use of mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection. Am J Transplant 2003; 3:68.
  56. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996; 61:1029.
  57. Goldfarb-Rumyantzev AS, Smith L, Shihab FS, et al. Role of maintenance immunosuppressive regimen in kidney transplant outcome. Clin J Am Soc Nephrol 2006; 1:563.
  58. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet 1995; 345:1321.
  59. Remuzzi G, Lesti M, Gotti E, et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet 2004; 364:503.
  60. Burke GW, Ciancio G. Show me the money--immunosuppression in kidney transplantation. Lancet 2004; 364:481.
  61. Leroy C, Rigot JM, Leroy M, et al. Immunosuppressive drugs and fertility. Orphanet J Rare Dis 2015; 10:136.
  62. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004; 4:231.
  63. Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 2004; 4:237.
  64. Budde K, Knoll G, Curtis J, et al. Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPA, myfortic). Clin Nephrol 2006; 66:103.
  65. Salvadori M, Holzer H, Civati G, et al. Long-term administration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients. Clin Nephrol 2006; 66:112.
  66. Johnston A, He X, Holt DW. Bioequivalence of enteric-coated mycophenolate sodium and mycophenolate mofetil: a meta-analysis of three studies in stable renal transplant recipients. Transplantation 2006; 82:1413.
  67. Sollinger HW, Sundberg AK, Leverson G, et al. Mycophenolate mofetil versus enteric-coated mycophenolate sodium: a large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients. Transplantation 2010; 89:446.
  68. Langone AJ, Chan L, Bolin P, Cooper M. Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study. Transplantation 2011; 91:470.
  69. Denhaerynck K, Dobbels F, Cleemput I, et al. Prevalence, consequences, and determinants of nonadherence in adult renal transplant patients: a literature review. Transpl Int 2005; 18:1121.
  70. Pinsky BW, Takemoto SK, Lentine KL, et al. Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression. Am J Transplant 2009; 9:2597.
  71. Didlake RH, Dreyfus K, Kerman RH, et al. Patient noncompliance: a major cause of late graft failure in cyclosporine-treated renal transplants. Transplant Proc 1988; 20:63.
  72. Meier-Kriesche HU, Steffen BJ, Chu AH, et al. Sirolimus with neoral versus mycophenolate mofetil with neoral is associated with decreased renal allograft survival. Am J Transplant 2004; 4:2058.
  73. Meier-Kriesche HU, Schold JD, Srinivas TR, et al. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant 2005; 5:2273.
  74. Srinivas TR, Schold JD, Guerra G, et al. Mycophenolate mofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation. Am J Transplant 2007; 7:586.
  75. Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev 2006; :CD004290.
  76. Lim WH, Eris J, Kanellis J, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant 2014; 14:2106.
  77. Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 2014; 349:g6679.
  78. Pascual J, Berger SP, Witzke O, et al. Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation. J Am Soc Nephrol 2018; 29:1979.
  79. Budde K, Becker T, Arns W, et al. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 2011; 377:837.
  80. Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87:233.
  81. Hahn D, Hodson EM, Hamiwka LA, et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev 2019; 12:CD004290.
  82. Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol 2010; 21:1587.
  83. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10:535.
  84. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant 2010; 10:547.
  85. Larsen CP, Grinyó J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation 2010; 90:1528.
  86. Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant 2011; 11:66.
  87. Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant 2012; 12:630.
  88. Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant 2012; 12:210.
  89. Rostaing L, Vincenti F, Grinyó J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant 2013; 13:2875.
  90. Charpentier B, Medina Pestana JO, Del C Rial M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys. Am J Transplant 2013; 13:2884.
  91. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med 2016; 374:333.
  92. Rostaing L, Massari P, Garcia VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol 2011; 6:430.
  93. Masson P, Henderson L, Chapman JR, et al. Belatacept for kidney transplant recipients. Cochrane Database Syst Rev 2014; :CD010699.
  94. Woodle ES, Kaufman DB, Shields AR, et al. Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial. Am J Transplant 2020; 20:1039.
  95. Florman S, Pestana JM, Rial M, et al. Final results from the BENEFIT-EXT trial: A 7-year follow-up of Belatacept treated patients. Am J Transplant 2015; 15(S3):1.
  96. de Graav GN, Baan CC, Clahsen-van Groningen MC, et al. A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation. Transplantation 2017; 101:2571.
  97. Kaufman DB, Woodle ES, Shields AR, et al. Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. Clin J Am Soc Nephrol 2021; 16:1387.
  98. Grinyó JM, Del Carmen Rial M, Alberu J, et al. Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial. Am J Kidney Dis 2017; 69:587.
  99. Darres A, Ulloa C, Brakemeier S, et al. Conversion to Belatacept in Maintenance Kidney Transplant Patients: A Retrospective Multicenter European Study. Transplantation 2018; 102:1545.
  100. Bertrand D, Chavarot N, Gatault P, et al. Opportunistic infections after conversion to belatacept in kidney transplantation. Nephrol Dial Transplant 2020; 35:336.
  101. Chavarot N, Divard G, Scemla A, et al. Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept. Am J Transplant 2021; 21:2448.
  102. Budde K, Prashar R, Haller H, et al. Conversion from Calcineurin Inhibitor- to Belatacept-Based Maintenance Immunosuppression in Renal Transplant Recipients: A Randomized Phase 3b Trial. J Am Soc Nephrol 2021; 32:3252.
  103. Divard G, Aubert O, Debiais-Deschamp C, et al. Long-Term Outcomes after Conversion to a Belatacept-Based Immunosuppression in Kidney Transplant Recipients. Clin J Am Soc Nephrol 2024; 19:628.
  104. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 2007; 46:13.
  105. Kuypers DR. Immunosuppressive drug monitoring - what to use in clinical practice today to improve renal graft outcome. Transpl Int 2005; 18:140.
  106. Rupprecht K, Schmidt C, Raspé A, et al. Bioavailability of mycophenolate mofetil and enteric-coated mycophenolate sodium is differentially affected by pantoprazole in healthy volunteers. J Clin Pharmacol 2009; 49:1196.
  107. Schaier M, Scholl C, Scharpf D, et al. Proton pump inhibitors interfere with the immunosuppressive potency of mycophenolate mofetil. Rheumatology (Oxford) 2010; 49:2061.
  108. Kees MG, Steinke T, Moritz S, et al. Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers. J Clin Pharmacol 2012; 52:1265.
  109. Knorr JP, Sjeime M, Braitman LE, et al. Concomitant proton pump inhibitors with mycophenolate mofetil and the risk of rejection in kidney transplant recipients. Transplantation 2014; 97:518.
  110. Doesch AO, Mueller S, Konstandin M, et al. Proton pump inhibitor co-medication reduces active drug exposure in heart transplant recipients receiving mycophenolate mofetil. Transplant Proc 2010; 42:4243.
  111. Miura M, Satoh S, Inoue K, et al. Influence of lansoprazole and rabeprazole on mycophenolic acid pharmacokinetics one year after renal transplantation. Ther Drug Monit 2008; 30:46.
  112. Gabardi S, Olyaei A. Evaluation of potential interactions between mycophenolic acid derivatives and proton pump inhibitors. Ann Pharmacother 2012; 46:1054.
  113. Kofler S, Shvets N, Bigdeli AK, et al. Proton pump inhibitors reduce mycophenolate exposure in heart transplant recipients-a prospective case-controlled study. Am J Transplant 2009; 9:1650.
  114. Kiberd BA, Wrobel M, Dandavino R, et al. The role of proton pump inhibitors on early mycophenolic acid exposure in kidney transplantation: evidence from the CLEAR study. Ther Drug Monit 2011; 33:120.
  115. Rissling O, Glander P, Hambach P, et al. No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study. Br J Clin Pharmacol 2015; 80:1086.
  116. Gregoor PJ, de Sévaux RG, Hené RJ, et al. Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients. Transplantation 1999; 68:1603.
  117. Smak Gregoor PJ, van Gelder T, Hesse CJ, et al. Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study. Nephrol Dial Transplant 1999; 14:706.
  118. van Hest RM, Mathot RA, Pescovitz MD, et al. Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol 2006; 17:871.
  119. Al Sagheer T, Enderby CY. Determining the conversion ratios for oral versus sublingual administration of tacrolimus in solid organ transplant recipients. Clin Transplant 2019; 33:e13727.
Topic 7356 Version 55.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟