Introduction
Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episodes and loss of the renal allograft. The optimal regimen of both induction and maintenance therapy has not been established. However, most centers rely on a triple IS after induction with either interleukin-2 receptor antibodies (IL2-RA) or anti-thymocyte globulin (ATG). This minireview focuses on clinical standards concerning IS in general and management of complications such as malignancies, diabetes, infections and other special situations.
Induction
Induction therapy is administered before, during or after renal transplantation. Two drugs are mainly used: the IL2-RA basiliximab and ATG. A number of clinical studies highlighted that the use of induction therapy in combination with standard maintenance IS is superior in reducing renal allograft rejection and graft failure compared to maintenance therapy alone [1‐4]. The only exceptions are Caucasian recipients of full-house-identical organs and potential patients already receiving maintenance IS after solid organ transplantation other than kidney [5], while in the latter setting some nephrologists also administer IL2-RA. IL-2-RA and ATG had similar efficacy concerning graft loss and clinically diagnosed acute rejection. Biopsy-proven acute rejection rates were slightly higher with IL2-RA (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.01–1.67). However, less side effects, particularly cytomegalovirus (CMV) disease and malignancies, made IL-2-RA the first choice in induction therapy [6, 7].
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ATG was superior over IL2-RA in the setting of high immunologic risk, which includes among other factors a higher number of human leukocyte antigen (HLA) mismatches, young donor age, high recipient age, panel reactive antibody status >0%, preformed donor specific antibodies, ABO-incompatible renal transplantation, delayed graft function and cold ischemia time >24 h [3, 7].
Alemtuzumab, a humanized anti-CD52 antibody, is an infrequently and not routinely used induction therapy in kidney transplantation, while it is approved for the treatment of relapsing–remitting multiple sclerosis in Europe and chronic lymphocytic leukemia in the US. Furthermore, alemtuzumab-treated patients had similar transplant failure rates compared to basiliximab [8], but worse graft survival rates and more chronic allograft nephropathy compared to ATG, under a maintenance IS without steroids [9]. Additionally, several groups have described occurrence of autoimmune diseases after alemtuzumab, e.g. anti-glomerular basement membrane disease [10].
Maintenance
The most frequently used substances for maintenance IS are glucocorticoids, antimetabolites such as azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), calcineurin inhibitors (CNI) such as cyclosporine A (CsA) or tacrolimus (Tac), mTOR inhibitors (mTORi) such as everolimus and sirolimus or the co-stimulation blocker belatacept. Kidney Disease-Improving Global Outcomes (KDIGO) suggests a triple combination consisting of CNIs, antimetabolites and corticosteroids for the majority of patients. In particular, the first-line recommended triple regimen is Tac, mycophenolate and corticosteroids. Patients with low immunological risk and induction therapy may be treated with a dual combination of Tac and MMF after rapid corticosteroid discontinuation within the first week [7]. Patients with Tac-related side effects, e.g. tremor, headache, diarrhea, dyspepsia, vomiting or alopecia may be switched to CsA, which—on the other hand—more frequently induces hirsutism, gingival hyperplasia and hypertension [11]. Target C0 levels of Tac and CsA are 7–10 and 150–300 ng/ml in the first 1–3 months and 5–7 and 50–150 ng/ml in subsequent months, respectively [7, 12].
Mycophenolate is the first-line antimetabolic agent as it was shown to be superior to azathioprine in preventing acute rejections with fewer side effects [13]. Most centers switch from MMF to EC-MPS in case of gastrointestinal side effects or generally prefer EC-MPS rather than MMF, which are similar in efficacy and safety [14, 15]. Mycophenolate is generally avoided in female recipients of childbearing age without sufficient contraceptive measures, whereas a dose reduction is mostly sufficient in other complications such as viral infections (as discussed below).
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Glucocorticoids may be withdrawn within the first week after renal transplantation in low immunological risk patients after induction therapy only [7]. The long-term maintenance dose usually is 5 mg prednisone equivalent. Withdrawal of glucocorticoids is not associated with improvement of insulin sensitivity [16] and is associated with recurrence of glomerulonephritis [17] and higher myelosuppressive effects of azathioprine, MMF and EC-MPS. Furthermore, late withdrawal increases the risk of acute rejection [18, 19].
Some patients do not tolerate CNIs due to nephrotoxic or other adverse effects. Alternative immunosuppressive regimens are mainly based on either belatacept or mTORi. In patients with CNI nephrotoxicity without contraindication for belatacept (e.g. seronegativity for Epstein-Barr virus [EBV]) we switch to belatacept as various studies have shown superior renal allograft function compared to CsA without significant safety concerns [20‐22]. Of note, belatacept is approved for IS in renal transplant recipients after induction with IL2-RA in combination with mycophenolate and corticosteroids. Compared to CNIs, mTORI had no significant difference in allograft and patient survival with higher rates of bone marrow suppression or dyslipidemia [23]. Similar results were published in patients converted from CNIs to mTORi plus a higher risk of acute rejection (relative risk [RR] 1.72, 95% CI 1.34–2.22) [24]. Hence, only in EBV-negative patients with an estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73 m2, a urinary protein-creatinine ratio (PCR) < 0.4 g/g AND a rationale for mTOR inhibitors is a switch to either everolimus or sirolimus performed, although the eGFR and PCR threshold might slightly vary between institutions [24‐27].
Take home message: The standard IS regimen consists of induction with either IL2-RA or ATG followed by a triple maintenance therapy consisting of Tac (or belatacept in case of CNI nephrotoxicity), mycophenolate and steroids.
Complications
Malignancy—non-melanoma skin cancer
The long-term risk for malignancy in general is increased (standardized incidence ratio [SIR] 2.1, 95% CI 2.06–2.14) in solid organ recipients compared to the general population [28]. The risks for Kaposi sarcoma (SIR 61), non-melanoma skin cancer (NMSC; SIR 13.9), non-Hodgkin lymphoma (NHL; SIR 7.5) and liver cancer (SIR 11.6) are most significantly increased. Reduction of IS may result in tumor regression in some cases; however, the optimal regimen has not been established. Treatment with low doses of CsA and azathioprine resulted in an approximately 35% reduction of cases with squamous or basal cell skin cancers compared to normal doses. However, acute graft rejection was increased by 8.7-fold, but graft survival rates were similar [29]. In general, reduction of IS increases the risk for rejection episodes, which commonly are treated at least by high doses of steroids plus an increase of IS. Hence, the potential risks or benefits of modifying IS must be carefully assessed on an individual basis. In 2006, Otley et al. published a consensus statement for reduction of IS in transplant-associated skin cancer [30]. In brief, a mild reduction of IS is proposed in patients with up to 25 NMSCs per year or stage 1A/B melanoma. Moderate reduction of IS is suggested in patients with a 3-year skin cancer mortality of 10–25% or stage II A/B melanoma and a severe reduction is proposed only in patients with metastatic skin cancer or stage >IIC melanoma.
Another modification of IS is to switch from CNI to mTORi. In a meta-analysis of 21 randomized trials of 5879 kidney and kidney–pancreas allograft recipients switch to sirolimus resulted in a significant reduction of NMSC risk (HR 0.44, 95% CI 0.30–0.63). Interestingly, patients on de novo sirolimus had the same risk compared to CNI-treated patients, suggesting that switching from CNI to mTORi is superior over prophylactic administration of mTORi-based IS in patients at risk for NMSC. However, the same study revealed a 43% higher risk of death (predominantly cardiovascular and infection-related) in patients on sirolimus [31]. A 47 and 37% increase of deaths was found also in an observational trial of 9353 kidney transplant patients on sirolimus and everolimus, respectively [32]. In a small study the decrease of new squamous cell cancer was not statistically significant [33].
Take home message: Modification of IS may result in reduced risk for NMSC but results in higher graft rejection rates and—in case of mTORi—deaths.
Post-transplant lymphoproliferative disorders
Post-transplant lymphoproliferative disorders (PTLDs) appear mostly related to the presence of EBV but EBV-negative disease may also occur. In general, EBV surveillance is performed in many centers and most nephrologists would reduce IS in case of EBV reactivation. In this context, it is interesting that the multivariate-adjusted relative risk for PTLDs was shown to be reduced by 38% for every 30 days of ganciclovir use after renal transplantation in 100 PTLD cases matched to 375 controls [34].
Treatment options are reduction of IS, rituximab, chemotherapy, radiation therapy or a combination of these. While polyclonal B cell proliferations (early lesions) are usually treated by reduction of IS, rituximab is added in patients with CD20+ polymorphic PTLDs, who do not meet all criteria for B‑ or T‑cell lymphomas. In monomorphic PTLDs a combination of the two mentioned measures with chemotherapy is usually administered. The definitive protocol depends on patients’ age and status, tumor load, laboratory findings, organ functions (heart, kidney, liver), PTLD subtype and may vary from institution to institution.
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Reduction of IS is usually performed in almost all patients with PTLDs. Most early lesions improve significantly within 5 weeks [35, 36]. The optimal regimen of reduced IS is not known. Guidelines from the BTS and Mayo Clinic suggest a reduction to 25–50% from baseline for kidney allograft recipients [37, 38]. However, complete withdrawal of CNIs was associated with reduced graft (HR 3.07, 95% CI 1.04–9.09) and patients’ survival (HR 4.00, 95% CI 1.77–9.04) in a multivariate analysis of a retrospective multicenter study [39].
Diabetes
Post-transplant diabetes mellitus (PTDM) is a frequent complication after kidney transplantation. PTDM patients have higher blood glucose values in the afternoon compared to non-transplanted diabetic patients. Despite that fact, diagnostic criteria of PTDM are the same as in otherwise healthy individuals [40]. Concerning IS, CNIs (Tac more than CsA), sirolimus and corticosteroids are considered to be diabetogenic. Steroids are usually not tapered off in the setting of PTDM, since the benefit of patients after renal transplantation mainly relies on preserved kidney function. Tac remains the first choice as mainstay of IS as 70% of Caucasian patients with early PTDM were able to discontinue insulin on Tac plus glucocorticoids [41] with the exception of specific indications for CsA or mTORi. Tac resulted in similar patient and graft survival rates despite higher PTDM incidence when compared to CsA [42]. Sirolimus is generally not recommended [43] in patients at risk for PTDM. Of note, in patients with pre-existing diabetes the immunosuppressive regimen should not be tailored to better diabetic control but to optimal kidney allograft survival (as stated above: Tac, mycophenolate, corticosteroids) [7, 44]. A consensus statement nicely summarizes important issues on PTDM prevention, diagnosis and therapy [44]. Of note, patients with PTDM without a history of preformed diabetes mellitus might benefit from early administration of basal insulin and should not be treated primarily using sulfonylureas [44, 45].
Take home message: The immunosuppressive regimen should be tailored for optimal kidney allograft survival rather than better diabetic control.
Infections
Cytomegalovirus
Cytomegalovirus (CMV) frequently reactivates after kidney transplantation. CMV infection and disease are associated with increased risk of graft failure and death. CMV infections are diagnosed by PCR in blood of asymptomatic patients. CMV syndrome is defined as attributable symptoms in CMV-PCR positive patients, whereas those with tissue-invasive CMV disease additionally suffer from organ dysfunction (e.g. enteritis, colitis, nephritis, hepatitis, pneumonitis). The cornerstone of CMV management is prophylaxis using the antiviral drug valganciclovir. In case of infection, timely diagnosis and reduction/withdrawal of antimetabolites and—if not already started—administration of valganciclovir or ganciclovir are the relevant measures. The exact regimen depends mainly on each center’s practice: while some would stop antimetabolites and introduce antiviral therapy later, others reduce antimetabolites and start antiviral therapy immediately. In CMV syndrome or disease, antimetabolites are commonly withdrawn, antiviral therapy is started and additional therapies (i.e. CMV immune globulin) are administered. In ganciclovir-resistant CMV disease, foscarnet and cidofovir are alternative antiviral options, which however bear high nephrotoxic potential.
Polyomavirus
BK and JC viruses are the only two polyomaviruses associated with nephropathy after transplantation, i.e. tubulointerstitial nephritis and ureteral stenosis. Typically, at the first stage of BKV reactivation, BKV particles are only found in urine. If untreated over weeks to months, BKV progresses to detectable viral particles in plasma and finally BKV nephropathy (BKVN), which is associated with graft failure in 15–50%. Screening and preemptive reduction or withdrawal of the antimetabolite at onset of viremia prevents progression to BKVN in 95% of cases [46, 47] without increased risk of allograft rejection or loss. In case of BKV viremia and kidney allograft dysfunction, a kidney biopsy is performed in order to distinguish BKVN from rejection. In case of BKVN the pivotal role of decreased IS has been highlighted above and is recommended by the American Society of Transplantation [48, 49]. In addition to reduction of antimetabolites, CNI doses may be decreased or Tac may be switched to CsA, which also lowers mycophenolate concentrations [50], or sirolimus [51, 52] in cases with progressive BKV diseases. Additional therapies that may be administered are immunoglobulin preparations, which contain anti-BKV antibodies, leflunomide [53] or cidofovir [54]. Levofloxacin has no relevant antiviral effects in patients with BKV viremia [55, 56].
Take home message: CMV is best managed by prophylaxis. In case of reactivation of CMV or BKV the net-state of IS is reduced.
Pneumocystis jirovecii
Pneumocystis jirovecii pneumonia (PJP) was a well-known disease in solid organ recipient, which, however, has been almost completely eliminated since the introduction of prophylactic use of trimethoprim-sulfamethoxazole [57]. PJP prophylaxis is recommended for 3–6 months after kidney transplantation. Additional prophylactic administration for at least 6 weeks has been proposed for patients having received treatment for acute allograft rejection episodes [7].
Other infections
Although there are no randomized controlled trials, most centers have similar standards of care in this context. In patients with community-acquired infections who are otherwise stable, the immunosuppressive regimens remain unmodified. In patients, who are admitted to inpatient care or who require intravenous antibiotics most centers decrease or withhold the antimetabolite. In case of life-threatening infections low-dose glucocorticoids are continued while CNIs and antimetabolites are withheld.
Special situations
In general, IS is usually not changed for elective surgery. The important exception are patients treated with mTORi, which has to be withdrawn due to wound healing problems. The optimal alternative regimen is not known and obviously the presumed time for wound healing also influences the choice of regimen. While some centers prefer to continue the antimetabolite and slightly increase corticosteroids, others switch to a CNI-based regimen until wound healing is completed.
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Women of childbearing age without sufficient contraceptive measures should not be treated with mycophenolate. Pregnant women are switched from mTORi and/or mycophenolate to a CNI, azathioprine and corticosteroids.
Conflict of interest
H. Neuwirt, M. Rudnicki, P. Schratzberger, M. Pirklbauer, A. Kronbichler, and G. Mayer declare that they have no competing interests.
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