INTRODUCTION — Maintenance immunosuppressive therapy is administered to almost all kidney transplant recipients to help prevent acute rejection and the loss of the renal allograft. Although an adequate level of 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 overall risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression.
The optimal maintenance immunosuppressive therapy in kidney transplantation is not established. The major immunosuppressive agents that are available in various combination regimens are glucocorticoids (primarily oral prednisone), azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), cyclosporine (in nonmodified or modified [microemulsion] form), tacrolimus, everolimus, rapamycin (sirolimus), and belatacept [1-3].
Conventional maintenance regimens consist of a combination of immunosuppressive agents that differ by mechanism of action. This strategy minimizes morbidity and mortality associated with each class of agent while maximizing overall effectiveness. Such regimens may vary by patient, transplant center, and geographic area.
The regimens and agents used for maintenance immunosuppression following kidney transplantation will be reviewed in this topic. A discussion of induction therapy in kidney transplantation is presented separately. (See "Kidney transplantation in adults: Induction immunosuppressive therapy".)
OVERVIEW OF OUR APPROACH TO INITIAL MAINTENANCE THERAPY — Transplanting a kidney from a donor who is not an identical twin without administering immunosuppressive agents invariably results in allograft rejection and loss. Thus, maintenance immunosuppressive therapy is given to practically all recipients of renal allografts.
Our approach — We and most transplant centers use a maintenance regimen consisting of triple immunosuppression therapy with the following agents [3]:
●A calcineurin inhibitor (cyclosporine or tacrolimus). (See 'Selection of a calcineurin inhibitor' below.)
●An antimetabolite (azathioprine, mycophenolate mofetil [MMF], or enteric-coated mycophenolate sodium [EC-MPS]). (See 'Selection of an antimetabolic agent' below.)
●Prednisone. (See 'Dosing of glucocorticoids' below.)
This is consistent with the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for kidney transplantation [4]. Our approach is based upon 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 [5-8].
We do not routinely use a mammalian (mechanistic) target of rapamycin (mTOR) inhibitor or belatacept as part of an initial maintenance immunosuppression regimen. However, we use an mTOR inhibitor or belatacept as an alternative agent in patients who cannot continue taking a calcineurin inhibitor due to toxicity, who develop a new cancer after transplantation, or who are noncompliant with therapy. (See 'Patients who develop toxicity from calcineurin inhibitors' below and 'Patients who develop a new cancer' below and 'Patients who are not compliant with therapy' below and "Liver transplantation in adults: Overview of immunosuppression".)
Exceptions to our approach include:
●In White recipients of human leukocyte antigen (HLA) two-haplotype-identical, living, related allografts, we use triple therapy for the first three to six months posttransplant, then switch to dual therapy with glucocorticoids plus an antimetabolite (EC-MPS, MMF, or azathioprine) [9].
●In African American, two-haplotype-identical, living, related recipients, we use triple therapy with glucocorticoids, an antimetabolite, and low-dose calcineurin inhibitors (tacrolimus trough levels of 3 to 5 ng/mL or cyclosporine trough levels of 50 to 100 ng/mL) [10].
●Recipients of HLA-identical allografts from a monozygotic twin can be treated with immunosuppression for one to three months. They are subsequently maintained without immunosuppressive medication, given that the allograft and recipient are immunologically identical [11-14].
The 2009 KDIGO guidelines also suggest that, among patients at low immunologic risk and who receive induction therapy, prednisone should be discontinued during the first week after transplantation [4]. This is based upon the desire to minimize long-term glucocorticoid exposure, thereby decreasing the risk of adverse effects with this agent. However, we do not agree with this recommendation and continue low-dose glucocorticoid therapy in all patients, regardless of risk for acute rejection. (See "Kidney transplantation in adults: Withdrawal or avoidance of glucocorticoids after kidney transplantation".)
When and how we initiate maintenance therapy — In patients undergoing kidney transplantation and receiving induction therapy with rabbit antithymocyte globulin (rATG)-Thymoglobulin, we initiate maintenance immunosuppressive therapy preoperatively by administering EC-MPS and glucocorticoids. We give EC-MPS at 360 mg orally upon inpatient admission to the floor. Postoperatively, we give EC-MPS at 720 mg orally twice daily until a therapeutic tacrolimus level is achieved, then we decrease EC-MPS to 360 mg orally twice daily. Methylprednisolone at 7 mg/kg (maximum dose of 500 mg) is administered intravenously in the operating room, followed by oral prednisone (1 mg/kg per day for the first week after transplantation, then tapered by the fifth week posttransplant to 5 mg per day). Tacrolimus maintenance therapy begins on postoperative day 1 with extended-release tacrolimus tablets at 0.08 mg/kg once per day, with doses adjusted to achieve a 12-hour trough level of 7 to 10 ng/mL for the first month and 3 to 7 ng/mL thereafter.
Some centers delay the introduction of a calcineurin inhibitor until the serum creatinine has decreased by 50 percent from the pretransplant value or until the patient has significant urine output. However, there is little evidence that delayed, rather than immediate, initiation of a calcineurin inhibitor results in lower rates of delayed graft function [5,15]. In addition, the 2009 KDIGO guidelines recommend that administration of calcineurin inhibitors should not be delayed until the onset of graft function [16].
PATIENT RISK STRATIFICATION — An important element in deciding maintenance immunosuppression is the identification of patients at high risk of acute rejection. With this view, more aggressive immunosuppression is justified in patients at significantly increased risk of rejection (see 'Initial maintenance immunosuppression in high-risk patients' below). In the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines, for example, risk factors for acute rejection include the following [4]:
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●African American ethnicity (in the United States)
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
Among patients at low immunologic risk (who have none of the above risk factors) and who also receive induction therapy, the KDIGO guidelines suggest that prednisone therapy should be discontinued during the first week after transplantation [4]. This is based upon the desire to minimize long-term glucocorticoid exposure, thereby decreasing the risk of adverse effects with this agent. However, we do not agree with this recommendation and continue low-dose glucocorticoid therapy in all patients, regardless of risk for acute rejection. (See "Kidney transplantation in adults: Withdrawal or avoidance of glucocorticoids after kidney transplantation".)
INITIAL MAINTENANCE IMMUNOSUPPRESSION IN HIGH-RISK PATIENTS — In patients who are high risk for acute allograft rejection (see 'Patient risk stratification' above), we administer a maintenance regimen consisting of triple immunosuppression therapy. This includes a calcineurin inhibitor (tacrolimus), an antimetabolite (mycophenolate), and prednisone.
We prefer a triple-agent regimen that includes a calcineurin inhibitor and an antimetabolite (typically mycophenolate), rather than one that includes a calcineurin inhibitor and a non-antimetabolite (eg, a mammalian [mechanistic] target of rapamycin [mTOR] inhibitor), because studies have shown benefit with triple regimens containing mycophenolate as compared with those containing an mTOR inhibitor [17,18]. In addition, the use of mTOR inhibitors as part of initial maintenance therapy is limited by early posttransplant complications associated with these agents, including delayed allograft function, poor wound healing, and an increased incidence of lymphoceles. However, some transplant centers continue to use an mTOR inhibitor in triple-therapy regimens, often in place of a calcineurin inhibitor or antimetabolic agent, or with a low-dose calcineurin inhibitor without an antimetabolic agent.
Selection of a calcineurin inhibitor — Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T cells. By inhibiting cytokine gene transcription, calcineurin inhibitors suppress T cell and T cell-dependent B cell activation. Either cyclosporine or tacrolimus is used in over 90 percent of kidney transplant recipients in the United States, with tacrolimus being more popular (92 versus 2 percent use) [19,20]. (See "Pharmacology of cyclosporine and tacrolimus".)
In most patients undergoing kidney transplant, we prefer tacrolimus because it is associated with decreased acute rejection rates and similar overall costs [6,21]. This is consistent with the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [4]. In addition, despite higher rates of new-onset diabetes after transplant (NODAT), 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.
Cyclosporine may be used in patients who have or who are predisposed to tacrolimus-associated toxicity (see 'Toxicity of tacrolimus versus cyclosporine' below). In these rare cases, belatacept or an mTOR inhibitor could also serve as alternative immunosuppression, although this has not been well studied. (See 'Patients who develop toxicity from calcineurin inhibitors' below and "Liver transplantation in adults: Overview of immunosuppression".)
The dosing of tacrolimus and cyclosporine among kidney transplant recipients is discussed separately. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Dose and administration'.)
Tacrolimus versus cyclosporine
Efficacy of tacrolimus versus cyclosporine — Among kidney transplant recipients, tacrolimus is more effective than nonmodified and modified cyclosporine at lowering the rate of acute rejection [6,7,22-27]. Overall, allograft and patient survival rates are similar with the two agents [8,21-25,27-29], although some studies have shown superior allograft survival with tacrolimus [6,7]. The following studies illustrate the range of findings:
●In a 2005 meta-analysis and meta-regression of 30 trials (4102 patients) comparing tacrolimus and cyclosporine (nonmodified and modified), tacrolimus significantly lowered the risk of allograft loss at six months (relative risk [RR] 0.56, 95% confidence interval [CI] 0.36-0.86) [6]. The benefit from tacrolimus was diminished when used at higher doses, possibly due to increased rates of calcineurin inhibitor toxicity and infection. Allograft loss at later time points also favored tacrolimus (RR 0.77 [CI 0.58-1.02] at one year, 0.74 [0.46-1.21] at two years, and 0.71 [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 superior allograft survival and fewer rejections versus standard and low-dose cyclosporine-based regimens [7]. However, significantly higher rates of NODAT developed in patients receiving low-dose tacrolimus (8 percent) versus those receiving standard-dose cyclosporine (6 percent), low-dose cyclosporine (4 percent), and low-dose sirolimus (7 percent).
●In another trial, 560 patients were randomly assigned to tacrolimus or modified cyclosporine plus azathioprine and glucocorticoids [25]. Tacrolimus significantly lowered the rates of acute rejection (20 versus 37 percent) and glucocorticoid-resistant rejection (9 versus 21 percent). At two years, the composite endpoint of allograft loss, patient death, and biopsy-proven acute rejection was significantly lower with tacrolimus (26 versus 43 percent).
Toxicity of tacrolimus versus cyclosporine — Tacrolimus has a toxicity profile that is slightly different from that of cyclosporine. Both short- and long-term studies in liver and kidney transplant recipients suggest that the acute and chronic nephrotoxicity of tacrolimus and cyclosporine are similar [30]. (See "Cyclosporine and tacrolimus nephrotoxicity".)
Reported differences in nonrenal toxicity with tacrolimus as compared with cyclosporine include [6,31-34] (see "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'):
●More prominent neurologic side effects such as tremor and headache
●More frequent incidence of NODAT
●More frequent diarrhea, dyspepsia, and vomiting
●More frequent alopecia
●Less frequent hirsutism, gingival hyperplasia, and hypertension
In addition, tacrolimus but not cyclosporine has rarely been reported to induce a hypertrophic cardiomyopathy [31,32,35-43] and severe neutropenia.
The role of tacrolimus in causing NODAT and in patients with cyclosporine nephrotoxicity, as well as other issues relating to tacrolimus toxicity, are discussed in detail separately (see "Kidney transplantation in adults: Posttransplantation diabetes mellitus" and "Kidney transplantation in adults: Chronic allograft nephropathy" and "Kidney transplantation in adults: BK polyomavirus-associated nephropathy"). In addition, converting from cyclosporine to tacrolimus may provide significant benefits in serum lipid levels. (See "Kidney transplantation in adults: Lipid abnormalities after kidney transplantation".)
To minimize these side effects, cyclosporine is sometimes used in place of tacrolimus. A paucity of data exists concerning the efficacy of substituting cyclosporine for tacrolimus among kidney transplant recipients initially treated with a tacrolimus-based immunosuppressive regimen. A short-term study found that, among stable patients, this conversion was safe without the induction of rejection [44]. It is unclear if this conversion is similarly safe in patients with intolerable adverse effects resulting from tacrolimus.
Immediate-release versus extended-release tacrolimus — In addition to standard immediate-release tacrolimus, there are two extended-release formulations of tacrolimus (capsules [Astagraf] and tablets [Envarsus]) designed for once-daily administration. We typically use extended-release tacrolimus rather than immediate-release formulations because of equal efficacy and fewer adverse effects (eg, tremor, alopecia, and neurotoxicity).
Multiple trials have demonstrated comparable efficacy and safety between immediate-release tacrolimus and extended-release tacrolimus capsules [45,46] and tablets [47-50]. Some studies have suggested that tacrolimus levels are slightly lower (10 to 20 percent) among patients treated with extended-release tacrolimus capsules (Astagraf) compared with those treated with immediate-release tacrolimus [51,52]. Extended-release tacrolimus is associated with a higher bioavailability, lower peak concentrations, and a longer time to maximum concentration than immediate-release tacrolimus. The adverse effects of extended-release tacrolimus appear to be similar to those of immediate-release tacrolimus, with the exception of fewer tremors [47]. Although extended-release tacrolimus has the added benefit of a convenient once-daily dosing, rigorous studies evaluating patient compliance with extended-release tacrolimus preparations are lacking. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Tacrolimus'.)
Nonmodified versus modified cyclosporine — Cyclosporine 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 [53-58]. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Cyclosporine' and "Pharmacology of cyclosporine and tacrolimus", section on 'Pharmacokinetics'.)
In patients who are initiated on cyclosporine therapy, we and most centers administer modified cyclosporine because of equivalent efficacy and more convenient administration and monitoring compared with nonmodified cyclosporine [59]. Trials have confirmed that modified cyclosporine is equivalent to nonmodified cyclosporine for prevention of graft rejection, and no differences have been shown in graft or patient survival [60,61]. The efficacy and safety of converting patients from nonmodified cyclosporine to modified cyclosporine was evaluated in a multicenter, double-blind trial of 262 patients in the United States [62]. With careful monitoring, this conversion was as safe as continuing therapy with the nonmodified formulation. In addition, a lower incidence of adverse events occurred among those converted to modified cyclosporine as compared with those maintained with nonmodified cyclosporine. Similar findings were reported in a Canadian study [59].
Drug interactions with calcineurin inhibitors — An important consideration among patients maintained on tacrolimus or cyclosporine is that several drugs interfere with its metabolism and therefore may cause either overdosing, with deterioration of renal function, or underdosing, with an increased incidence of rejection (table 1 and table 2 and table 3). Reviewed briefly, the following agents increase blood levels of tacrolimus and cyclosporine:
●Calcium channel blockers – verapamil, diltiazem, nicardipine, and amlodipine
●Antifungal agents – ketoconazole, itraconazole, and fluconazole
●Antibiotics – erythromycin and clarithromycin
●Grapefruit juice
Common medications that decrease blood levels (by inducing hepatic metabolism) include:
●Anticonvulsants – barbiturates, phenytoin, and carbamazepine
●Antituberculous agents – isoniazid and rifampin
For additional information on drug interactions, use the Lexicomp drug interactions program provided by UpToDate.
Other nephrotoxins may worsen the renal toxicity of tacrolimus and cyclosporine, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, and amphotericin B. In addition, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (such as lovastatin) can cause rhabdomyolysis and, rarely, acute kidney injury when given with cyclosporine. This effect may be mediated at least in part by a cyclosporine-induced impairment in metabolism of the statin. Starting with small doses may obviate this problem, thereby allowing these drugs to be used together. Muscle toxicity is less common with some of the statins, particularly pravastatin, even when given with cyclosporine. The concomitant use of cyclosporine and simvastatin is contraindicated. (See "Kidney transplantation in adults: Lipid abnormalities after kidney transplantation".)
Target levels for calcineurin inhibitors — We routinely monitor whole-blood tacrolimus or cyclosporine levels among kidney transplant recipients [63]. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Drug monitoring'.)
In patients treated with tacrolimus, we monitor whole-blood 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively [4]. Our C0 target levels are the following:
●In patients who receive antilymphocyte-depleting agents (eg, rabbit antithymocyte globulin [rATG]-Thymoglobulin) for induction therapy:
•7 to 10 ng/mL for the first month after transplantation
•3 to 7 ng/mL for subsequent months
●In patients who do not receive antilymphocyte-depleting agents for induction therapy:
•8 to 10 ng/mL for months 1 to 3 after transplantation
•3 to 7 ng/mL for subsequent months
In most patients treated with cyclosporine, we monitor whole-blood 12-hour trough (C0) concentrations [4]. With this approach, our C0 target levels are the following:
●200 to 300 ng/mL in months 1 to 3 after transplantation
●50 to 150 ng/mL for subsequent months
Although monitoring of trough levels (12 hours postdose) of cyclosporine is common practice, there is a poor correlation between clinical outcome and drug exposure as assessed using this strategy. Thus, in some patients (eg, patients suspected of having poor cyclosporine absorption), we monitor two-hour postdose cyclosporine (C2) levels [63]. Among kidney transplant recipients, the C2 level may correlate more closely with exposure, with higher C2 concentrations being associated with decreased acute rejection rates in the first year posttransplant [64-66]. However, C2 monitoring is often more difficult and less convenient for the patient. Our C2 target levels are the following:
●800 to 1000 ng/mL in months 1 to 3 after transplantation
●400 to 600 ng/mL for subsequent months
Selection of an antimetabolic agent — Antimetabolic agents interfere with the synthesis of nucleic acids and inhibit the proliferation of both T and B lymphocytes. Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) is the antimetabolic agent used in more than 90 percent of kidney transplant recipients in the United States; azathioprine is rarely used [19]. However, MMF and EC-MPS are much more expensive than azathioprine. (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".)
We and most transplant centers administer mycophenolate (MMF or EC-MPS) as an antimetabolic agent to kidney transplant recipients rather than azathioprine. This is consistent with the 2009 KDIGO clinical practice guidelines, which suggest mycophenolate as the first-line antimetabolic agent [4]. Despite its increased cost, mycophenolate is preferred over azathioprine because of its superior ability to prevent acute rejection and better side effect profile [67]. (See 'Mycophenolate mofetil versus azathioprine' below.)
MMF and EC-MPS are similar in efficacy and safety [68,69]. 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) [70]. If patients tolerate neither MMF nor EC-MPS, we switch to azathioprine. (See 'Mycophenolate mofetil versus mycophenolate sodium' below.)
However, 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. 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 [71]. (See 'Patients who become pregnant' below.)
The dosing of EC-MPS is discussed above (see 'When and how we initiate maintenance therapy' above). If EC-MPS is not available, we initiate MMF at a dose of 1000 mg two times per day during the first hospital admission. Patients are discharged, usually at postoperative day 5, on 500 mg two times per day (particularly with tacrolimus [72,73]) or 1000 mg two times per day if the patient is receiving cyclosporine.
The usual maintenance dose for azathioprine is 1.5 mg/kg per day, although it is 2.5 mg/kg at some centers.
Mycophenolate mofetil versus azathioprine
Efficacy of MMF versus azathioprine — As noted above, we and most transplant centers administer mycophenolate (MMF or EC-MPS) as an antimetabolic agent to kidney transplant recipients rather than azathioprine. This practice 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 [67,74-84].
The best data come from a 2016 meta-analysis and two blinded randomized trials that were included in the meta-analysis:
●A systematic review of 23 trials involving 3301 kidney transplant recipients compared the efficacy and safety of MMF versus azathioprine [67]. 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.
●One blinded trial compared mycophenolate (2 or 3 g/day in divided doses) to azathioprine (1 to 2 mg/kg/day) in 499 patients who were also treated with cyclosporine, prednisone, and horse antithymocyte globulin [74]. Although 6- and 12-month patient and graft survival were similar in the two groups, mycophenolate was associated with fewer first rejection episodes (18 to 20 versus 38 percent with azathioprine) and fewer episodes of rejection or treatment failure manifested by graft loss, death, or withdrawal from therapy (31 versus 48 percent). At three years posttransplant, graft and patient survival, renal function, and safety were similar among the three treatment groups [79].
●The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group trial compared the effectiveness of MMF at two doses, 3 g/day and 2 g/day, with azathioprine (100 to 150 mg/day) in 503 kidney transplant patients [77]. Each group was also treated with equivalent doses of glucocorticoids and cyclosporine. Compared with azathioprine, MMF resulted in lower rates of treatment failure at six months (35 and 38 percent versus 50 percent) and acute rejection (16 and 20 percent versus 36 percent), a decreased use of antilymphocyte antibody for severe or steroid-resistant rejection episodes (5 and 9 percent versus 15 percent), and a nonsignificant trend toward improved graft survival at one year.
At three years, both MMF groups continued to show a nonsignificant trend toward better graft survival and a lower rate of graft loss from rejection as compared with the azathioprine group [85]. However, a 15-year follow-up study of 133 Australian patients who participated in the initial trial reported no difference in mortality, allograft survival, cancer incidence, or kidney function after the first year (underpowered to detect a difference with this number of patients) [86]. By five years, 42 percent of patients on MMF had switched to azathioprine, whereas few patients assigned to receive azathioprine crossed over to mycophenolate. Despite this large crossover, intention-to-treat and as-treated analyses yielded similar results, which supports the use of azathioprine, which is substantially less expensive than mycophenolate.
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 antimetabolic agent plus a calcineurin inhibitor.
Toxicity of MMF versus azathioprine — The adverse effects of azathioprine, MMF, and EC-MPS include dose-related bone marrow suppression and gastrointestinal disturbances. For azathioprine, other rare but serious adverse events such as pancreatitis and elevated liver transaminase levels may occur. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on '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.
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 "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)
Mycophenolate mofetil versus mycophenolate sodium — Persistent diarrhea, the most frequent adverse reaction to mycophenolate, is the principal reason underlying its discontinuation. Dose reduction and/or withdrawal of MMF due to gastrointestinal complications has been associated with an increased risk for rejection and allograft failure [87,88]. Mycophenolate sodium (EC-MPS), an enteric-coated formulation of mycophenolate, was developed to try to improve the upper gastrointestinal tolerability of mycophenolate.
EC-MPS and MMF are similar in both efficacy and safety [68,69,89-91]:
●In one study of 423 patients, EC-MPS at a dose of 720 mg twice daily was therapeutically equivalent to MMF at 1000 mg twice daily, with similar safety characteristics [68].
●In another one-year study of stable kidney transplant patients, comparable safety and efficacy measures permitted conversion from MMF to EC-MPS [69].
Some but not all studies have found that EC-MPS produced fewer gastrointestinal side effects. As an example, a multicenter trial in which patients with significant gastrointestinal complaints with MMF were converted to EC-MPS resulted in significantly fewer gastrointestinal symptoms and improved overall patient well-being [92]. Similar findings have been observed in other studies [93]. However, there were no significant differences in gastrointestinal side effects between the two agents in other studies [68,69].
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. We avoid splitting the total daily dose of EC-MPS to four times per day because of the lack of supporting pharmacokinetic data and increased risk of poor adherence. These perceived gastrointestinal benefits should be weighed with the cost savings associated with generic MMF, generic EC-MPS, or generic azathioprine.
Drug interactions with antimetabolic agents — Trough levels of mycophenolate appear to be lowered by the concurrent administration of cyclosporine [94-96]. This effect 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.
In patients who are receiving proton pump inhibitors, we prefer the use of EC-MPS, rather than MMF. Observational studies of transplant and nontransplant patients have suggested that coadministration of proton pump inhibitors and MMF may result in lower mycophenolic acid exposure, which could increase the risk of acute rejection [97-103]. However, other studies, including one small, prospective, crossover trial, have not supported these findings [104-106].
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 (AUC) 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.
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 "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)
For additional information on drug interactions, use the Lexicomp drug interactions program provided by UpToDate.
Target levels for antimetabolic agents — In the future, the measurement and monitoring of mycophenolate or 6-thioguanine concentrations may permit better immunosuppressive management [107-112]. We do not obtain these tests now, since they are not routinely available, reliable, or associated with efficacy or toxicity.
Dosing of glucocorticoids — There is no consensus on the optimal dose or maintenance schedule of glucocorticoids following kidney transplantation [4,113]. As part of a triple-agent immunosuppressive regimen, we administer methylprednisolone at 7 mg/kg (maximum of 500 mg) intravenously in the operating room, then initiate oral prednisone at a dose of 1 mg/kg per day (maximum dose of 80 mg) for the first three days posttransplant, which is then lowered to 20 mg/day for the first week. The daily dose is then tapered every week by 5 mg, resulting in 15 mg/day for one week, 10 mg/day for one week, and then 5 mg/day. In the absence of acute rejection, we generally reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation.
The use of long-term glucocorticoids may vary from center to center and patient to patient. According to the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) Annual Data Report from 2016, approximately 70 percent of patients receive glucocorticoids at the time of transplant, and 65 percent of patients remain on glucocorticoids at one year after transplant (figure 1) [114].
In an attempt to minimize toxicity and to decrease overall immunosuppression, slow tapering and ultimate withdrawal of glucocorticoids has also been attempted. We do not routinely discontinue or switch to alternate-day glucocorticoids unless the patient is having problems with side effects (such as new difficulties in controlling blood pressure or severe irritability or rage disorder) and has had stable renal allograft function with no episodes of acute rejection within the preceding 6 to 12 months. However, switching to alternate-day glucocorticoids does not necessarily reduce side effects associated with glucocorticoids. A reduction in the daily glucocorticoid dose to 2.5 mg daily may be attempted among otherwise stable patients who have adverse side effects attributed in part to glucocorticoids.
Withdrawal of glucocorticoids compared with continuance of 5 mg per day of prednisone is not associated with improvement in insulin sensitivity [115]. The removal of glucocorticoids may also magnify the myelosuppressive action of azathioprine, MMF, or MPA, and the white blood cell count must therefore be monitored carefully.
Glucocorticoid avoidance is also associated with increased risks of recurrent glomerulonephritis [116]. In one large, retrospective study, rapid glucocorticoid withdrawal was associated with a higher risk of recurrent glomerulonephritis (eg, focal segmental glomerulosclerosis, immunoglobulin A [IgA] nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, or polyangiitis with granulomatosis) compared with continued glucocorticoids (hazard ratio [HR] 4.86, 95% CI 2.34-10.07). This study showed no difference between groups in patient, graft, or death-censored graft survival, suggesting no benefit and possible harm from glucocorticoid avoidance in patients with a history of glomerulonephritis.
Glucocorticoid withdrawal or avoidance in kidney transplantation is discussed in detail separately. (See "Kidney transplantation in adults: Withdrawal or avoidance of glucocorticoids after kidney transplantation".)
INITIAL MAINTENANCE IMMUNOSUPPRESSION IN LOW-RISK PATIENTS — In patients who are not considered to be at high risk for acute rejection (see 'Patient risk stratification' above), we administer a maintenance regimen consisting of triple immunosuppression therapy. This includes a calcineurin inhibitor (cyclosporine or tacrolimus), an antimetabolite (azathioprine or mycophenolate), and prednisone. This approach is similar to the one we use for patients considered to be at high risk for acute rejection. (See 'Initial maintenance immunosuppression in high-risk patients' above.)
The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest that, among patients at low immunologic risk and who receive induction therapy, prednisone should be discontinued during the first week after transplantation [4]. This is based upon the desire to minimize long-term glucocorticoid exposure, thereby decreasing the risk of adverse effects with this agent. However, we do not agree with this recommendation and continue low-dose glucocorticoid therapy in all patients, regardless of risk for acute rejection. (See "Kidney transplantation in adults: Withdrawal or avoidance of glucocorticoids after kidney transplantation".)
Exceptions to our approach include:
●In White recipients of human leukocyte antigen (HLA) two-haplotype-identical, living, related allografts, we use triple therapy for the first three to six months posttransplant, then switch to dual therapy with glucocorticoids plus an antimetabolite (enteric-coated mycophenolate sodium [EC-MPS], mycophenolate mofetil [MMF], or azathioprine). Multiple studies have shown that these recipients are at significantly lower risk of rejection and allograft loss [9,117].
●In African American, two-haplotype-identical, living, related recipients, we use triple therapy with glucocorticoids, an antimetabolite, and low-dose calcineurin inhibitors (tacrolimus trough levels of 3 to 5 ng/mL or cyclosporine trough levels of 50 to 100 ng/mL) since these patients are at increased risk for early acute rejection compared with White recipients [10].
●Recipients of HLA-identical allografts from a monozygotic twin can be treated with immunosuppression for one to three months. They are subsequently maintained without immunosuppressive medication, given that the allograft and recipient are immunologically identical [11-14].
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. 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 compliant or who cannot afford to pay for the medications. (See 'Patients who are not compliant with 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.
Patients who develop toxicity from calcineurin inhibitors — Although calcineurin inhibitors 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 mammalian (mechanistic) 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. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects' and "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors" and "Transplantation immunobiology", section on 'CD28, B7, and CTLA4'.)
Our approach is as follows:
●In patients who have biopsy-proven calcineurin inhibitor nephrotoxicity (without acute rejection), we typically discontinue the calcineurin inhibitor and switch to either an mTOR inhibitor (sirolimus or everolimus) or belatacept.
●In patients who develop other serious adverse effects (eg, neurotoxicity, thrombotic microangiopathy [TMA]) that can be attributed to calcineurin inhibitors, we first reduce the dose of the calcineurin inhibitor by 25 to 50 percent. If the adverse effects persist in spite of dose reduction, we discontinue the calcineurin inhibitor and switch to either an mTOR inhibitor (sirolimus or everolimus) or belatacept.
When converting from a calcineurin inhibitor to an mTOR inhibitor, the initial dose of sirolimus is 2 to 4 mg per day with target concentrations of 4 to 6 ng/mL. The initial dose of everolimus is 0.75 mg orally twice daily with target concentrations of 5 to 7 ng/mL.
When converting from a calcineurin inhibitor to belatacept, we administer belatacept at 5 mg/kg intravenously on day 0, weeks 2, 4, 6, 8, 12, 16, 20, and every four weeks thereafter. In patients with less serious calcineurin inhibitor-related adverse events (eg, tremor, alopecia), we reduce the calcineurin inhibitor dose by 50 percent at week 2, 75 percent from initial dose at week 3, and discontinue on week 4 [118]. In patients with serious calcineurin inhibitor adverse events (eg, TMA), discontinuation of calcineurin inhibitors may need to be immediate.
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. (See "Sirolimus (conventional): Drug information" and "Everolimus: Drug information".)
The efficacy and safety of mTOR inhibitors in kidney transplant recipients have been evaluated in multiple trials [119-125]. Most of these studies have examined the use of mTOR inhibitors as a replacement for either calcineurin inhibitors or antimetabolic agents or in combination with calcineurin inhibitors. 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 [119-121]. 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 calcineurin inhibitors or antimetabolic agents or in combination with calcineurin inhibitors [122]. There was no significant difference in allograft or patient survival with any comparison. Compared with patients who received a calcineurin inhibitor, those who received an mTOR inhibitor had better renal function for up to two years posttransplant but also had an increased risk of bone marrow suppression, dyslipidemia (relative risk [RR] 1.8, 95% confidence interval [CI] 1.1-3.0), and lymphoceles (RR 3.1, 95% CI, 1.6-5.9).
●Conversion from a calcineurin inhibitor to an mTOR inhibitor among kidney transplant recipients was evaluated in a systematic review of 29 randomized trials [123]. Patients who were converted from a calcineurin inhibitor 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 calcineurin inhibitor. 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 [124]. Compared with controls, sirolimus was associated with a decreased risk of malignancy (adjusted hazard ratio [HR] 0.60, 95% CI 0.39-0.93) but an increased risk of death (HR 1.43, 95% CI 1.21-1.71). The increased mortality was driven by increased cardiovascular and infection-related deaths in the sirolimus group.
Multiple studies have evaluated the efficacy and safety of belatacept in kidney transplant recipients [126-138]. These trials have encouraging results but many limitations. As an example, the first two trials discussed below did not compare belatacept with contemporary immunosuppression (ie, tacrolimus-based maintenance regimens). In addition, belatacept is expensive and must be administered intravenously.
●In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT), 686 recipients of a living or standard-criteria deceased donor kidney transplant were randomly assigned to more intensive (MI) belatacept, less intensive (LI) belatacept, or cyclosporine, in conjunction with mycophenolate and glucocorticoids; all patients received basiliximab as induction therapy [127,129,132,133,135,139]. At 12 months, patients treated with belatacept experienced a higher incidence and grade of acute rejection episodes (22 and 17 versus 7 percent in the MI, LI, and cyclosporine arms, respectively) but had superior renal function, a benefit that was sustained at seven years posttransplant (estimated glomerular filtration rate [eGFR] of 70 and 72 versus 45 mL/min/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). Posttransplant lymphoproliferative disorder (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 extended criteria donor (ECD) kidney transplant recipients, using the same study design as the one used in BENEFIT [128,129,131,134,140]. At 12 months, acute rejection rates were similar between groups. Similar to BENEFIT, patients treated with belatacept had better renal function at one, two, five, and seven years compared with those treated with cyclosporine. Rates of PTLD were also higher among patients treated with belatacept.
●A randomized, controlled trial compared belatacept with a tacrolimus-based, steroid-avoiding maintenance immunosuppression regimen [130]. Recipients of living and deceased donor renal allografts were randomly assigned to treatment with belatacept-mycophenolate mofetil (belatacept-MMF), belatacept-sirolimus, or tacrolimus-MMF. All patients received induction with rabbit antithymocyte globulin (rATG)-Thymoglobulin and a short course of glucocorticoids. Acute rejection rates were highest in the belatacept-MMF arm (12 percent), and the calculated GFR was 8 to 10 mL/min higher with either belatacept regimen than with tacrolimus-MMF.
●Another randomized, controlled trial of 40 kidney transplant recipients compared belatacept with a tacrolimus-based, steroid-containing maintenance regimen [141]. Patients were randomly assigned to belatacept or tacrolimus, combined with MMF and prednisolone; all patients received basiliximab as induction therapy. At one year posttransplant, the incidence of acute rejection was higher among patients who received belatacept compared with those who received tacrolimus (55 versus 10 percent, respectively). Graft loss, due to rejection, occurred in three patients, all in the belatacept group. There was no difference in graft function between the two groups.
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".)
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 (calcineurin inhibitor 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 noncompliant, and factors contributing to poor adherence should be assessed. The treatment of patients with acute T cell-mediated (cellular) rejection and antibody-mediated rejection (ABMR) 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 with recurrent primary renal disease — The modification of maintenance immunosuppression among patients with recurrent primary renal disease is discussed separately.
●(See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation".)
●(See "Membranous nephropathy and kidney transplantation", section on 'Recurrent membranous nephropathy'.)
●(See "Anti-GBM (Goodpasture) disease: Recurrence after transplantation".)
Patients who develop 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 "Treatment and prevention of post-transplant lymphoproliferative disorders" and "Malignancy after solid organ transplantation", section on 'Reduction in immunosuppression'.)
Patients who develop an 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. We usually restart the calcineurin inhibitor within one week from the time it was withheld but discontinue the antimetabolite indefinitely.
●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 hepatitis B, hepatitis C, cytomegalovirus (CMV), EBV, or BK viruses is discussed elsewhere.
●(See "Hepatitis C infection in kidney transplant candidates and recipients".)
●(See "Infection in the solid organ transplant recipient".)
●(See "Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients".)
Patients undergoing 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. 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 cyclosporine and tacrolimus", section on 'Switching formulations'.)
Patients who become pregnant — MMF, mycophenolate sodium, 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. (See "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Contraception' and "Kidney transplantation in adults: Sexual and reproductive health after kidney transplantation", section on 'Contraception'.)
Patients who are not compliant with therapy — Noncompliance is a risk factor for rejection and allograft loss [142-144]. Thus, every effort should be made to identify noncompliant patients early and provide them with appropriate counseling and assistance. In patients who are known to be noncompliant 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.
INVESTIGATIONAL THERAPIES — B cells play both a positive and negative role in kidney transplantation. By producing alloantibodies and secreting proinflammatory cytokines, such as interleukin (IL)-6, that activate alloreactive T cells, B cells promote humoral alloimmunity and negatively impact renal allograft survival. However, regulatory B cells produce IL-10 and may promote transplant tolerance. Thus, therapies that inhibit B cell effector function (eg, antibody secretion) and spare regulatory B cell function without increasing infection risk could be beneficial to transplant recipients.
B lymphocyte stimulator (BLyS; also known as B cell-activating factor [BAFF]) is a cytokine that promotes B cell survival and proliferation (see "The adaptive humoral immune response", section on 'TACI, BAFF, and APRIL'). High serum concentrations of BLyS in kidney transplant recipients have been associated with the development of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA), high concentrations of HLA antibodies, and an increased frequency of antibody-mediated rejection (ABMR) [145-147]. Inhibition of this pathway with belimumab, a human monoclonal antibody that inhibits the soluble form of BLyS, has been proposed as a therapeutic target in kidney transplantation. The safety and activity of belimumab, in addition to standard maintenance immunosuppression, was evaluated in a double-blind, randomized, placebo-controlled phase II trial of 28 kidney transplant recipients [148]. Patients were randomly assigned to receive intravenous belimumab (10 mg/kg) or placebo, administered at day 0 (day of transplant), 14, and 28, and then every four weeks for a total of seven infusions. All patients were given basiliximab as induction therapy and mycophenolate mofetil (MMF), tacrolimus, and prednisolone as maintenance immunosuppression. Primary endpoints included safety and the change in concentration of naïve B cells from baseline to week 24. The following results were noted:
●Belimumab effectively removed circulating free BLyS and decreased serum BLyS concentrations up to 12 weeks from the time of treatment discontinuation. Treatment with belimumab, compared with placebo, did not significantly reduce the number of naïve B cells at 24 weeks compared with baseline. However, a prespecified secondary analysis of patients who received at least five doses of study drug found belimumab-treated patients had a significant reduction in naïve B cell count at 28 weeks compared with placebo-treated patients.
●The frequency of serious adverse events was similar between patients who received belimumab and those who received placebo, and there was difference in the rates of serious infections between the two treatment arms.
●Patients treated with belimumab, compared with those treated with placebo, had a reduction in IL-6-producing B cells (29 versus 43 percent) and an increase in IL-10-producing B cells (4.6 versus 2.5 percent), suggesting that belimumab skewed the IL-10 to IL-6 ratio toward a more regulatory profile compared with the control.
Limitations to this trial included the small number of patients (n = 8) that received the per-protocol dosing regimen of belimumab and the exclusion of high-immunologic risk patients (patients with DSAs or sensitized patients). In addition, this trial was not powered to assess clinical endpoints, such as ABMR. Additional studies with larger populations are needed to determine if this agent, when used as an adjunct to standard immunosuppression, can provide clinical benefit to kidney transplant recipients.
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
●We recommend the administration of maintenance immunosuppressive therapy to kidney transplant recipients. The optimal immunosuppressive regimen is not established. The major immunosuppressive agents that are available in various combination regimens are glucocorticoids (primarily oral prednisone), azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), cyclosporine (in nonmodified or modified [microemulsion] form), tacrolimus, everolimus, sirolimus, and belatacept. (See 'Introduction' above.)
●In kidney transplant recipients who are considered to be at high risk for acute rejection, we recommend a maintenance regimen consisting of triple immunosuppression therapy with a calcineurin inhibitor, an antimetabolite, and prednisone rather than alternative regimens (Grade 1B). We aim for the following regimen and doses:
•Among the available calcineurin inhibitors, we suggest the administration of tacrolimus rather than cyclosporine (Grade 2B). Tacrolimus is associated with decreased acute rejection rates and is generally better tolerated than cyclosporine. We prefer extended-release tacrolimus tablets rather than immediate-release formulations because of equal efficacy and fewer adverse effects (eg, tremor, alopecia, and neurotoxicity). We initiate extended-release tacrolimus tablets on postoperative day 1 at 0.08 mg/kg once per day, with doses adjusted to achieve a 12-hour trough level of 7 to 10 ng/mL for the first month and 3 to 7 ng/mL thereafter. (See 'Selection of a calcineurin inhibitor' above.)
•Among the available antimetabolic agents, we suggest the administration of mycophenolate (MMF or EC-MPS) rather than azathioprine (Grade 2B). Despite its increased cost, 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. Thus, in these patients, we prefer to use azathioprine. (See 'Selection of an antimetabolic agent' above.)
We prefer EC-MPS over MMF because EC-MPS is similar in efficacy and safety and may be associated with fewer gastrointestinal side effects among certain groups of patients. We administer EC-MPS at 360 mg orally upon inpatient admission to the floor. Postoperatively, we give EC-MPS at 720 mg orally twice daily until a therapeutic tacrolimus level is achieved, then we decrease EC-MPS to 360 mg orally twice daily. (See 'Mycophenolate mofetil versus mycophenolate sodium' above.)
•We administer methylprednisolone at 7 mg/kg (maximum of 500 mg) intravenously in the operating room, then initiate oral prednisone at a dose of 1 mg/kg per day (maximum dose of 80 mg) for the first three days posttransplant, which is then lowered to 20 mg/day for the first week. The daily dose is then tapered every week by 5 mg, resulting in 15 mg/day for one week, 10 mg/day for one week, and then 5 mg/day. In the absence of acute rejection, we generally reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation. (See 'Dosing of glucocorticoids' above.)
●In kidney transplant recipients who are not considered to be at high risk for acute rejection, we administer a maintenance regimen consisting of triple immunosuppression therapy with a calcineurin inhibitor, an antimetabolite, and prednisone. This approach is similar to the one we use for patients considered to be at high risk for acute rejection. (See 'Initial maintenance immunosuppression in low-risk patients' above.)
Exceptions to our approach include the following:
•In White recipients of human leukocyte antigen (HLA) two-haplotype-identical, living, related allografts, we use triple therapy for the first three to six months posttransplant, then switch to dual therapy with glucocorticoids plus an antimetabolite (EC-MPS or azathioprine).
•In African American, two-haplotype-identical, living, related recipients, we use triple therapy with glucocorticoids, an antimetabolite, and low-dose calcineurin inhibitors (tacrolimus troughs of 3 to 5 ng/mL or cyclosporine troughs of 50 to 100 ng/mL).
•Recipients of HLA-identical allografts from a monozygotic twin can be treated with immunosuppression for one to three months. They are subsequently maintained without immunosuppressive medication.
●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. Complete withdrawal of all maintenance therapy is not recommended (except in recipients of 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.)
