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Editorials and Perspectives: Overview

Wound Healing Complications and the Use of Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation

A Critical Review of the Literature

Nashan, Björn1,3; Citterio, Franco2

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doi: 10.1097/TP.0b013e3182551021
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Abstract

Wound complications after kidney transplantation are a frequent occurrence (1–3), and although they do not generally affect graft or patient outcomes (4), they are a considerable source of morbidity (5), delaying hospital discharge (6) and requiring rehospitalization (7) or reoperation in up to a third of cases (8). Attention has recently focused on wound healing in light of the evidence showing impairment of the healing process in patients receiving the mammalian target of rapamycin (mTOR) inhibitor class of drug. Analyses (9, 10) of the association between mTOR inhibitors and wound healing have typically included all relevant randomized trials, including those that used early high-exposure regimens. In recent years, however, the dosing regimens for mTOR inhibitors have evolved considerably, with growing avoidance of loading doses, adoption of concentration-controlled dosing in combination with low-exposure calcineurin inhibitor (CNI) therapy, and targeting of successively lower blood concentrations. This article considers the question of whether modern dosing regimens for mTOR inhibitors remain an important risk factor for wound healing complications.

METHODOLOGY

Multiple searches of PubMed were performed based on a series of related terms to identify randomized trials of an mTOR inhibitor-based regimen versus at least one non–mTOR inhibitor control arm in which the occurrence of wound healing events was reported. The U.S. Food and Drug Administration database was searched for relevant data in open-access files on mTOR inhibitors.

WOUND HEALING IN THE KIDNEY TRANSPLANT POPULATION

Establishing the incidence of wound healing complications after kidney transplantation is challenging owing to the inconsistent reporting criteria, but studies from the 1990s and early 2000s have typically described an incidence of impaired wound healing in the range 15% to 20% (1, 2). Dehiscence rates of 2.5% to 3.6% have been observed relatively consistently in kidney transplant recipients (6, 7, 11), with wound infections in 5% to 8% of recipients (1, 7, 12, 13). Overall, the rate of surgical complications can range from 15% to 32% (14).

High body mass index (BMI) is the best-documented risk factor for disrupted wound healing in kidney transplant patients (1, 3, 7, 15–17). A multivariate analysis of data from a prospective, multicenter, randomized study of different immunosuppressive regimens found that every one-point increase in BMI was associated with a 19% increase in the odds of developing a wound complication (95% confidence interval [CI], 1.1–1.3; P=0.002) (15), but as in the general population (18–22), older age (1, 7, 23), diabetes mellitus (1, 7), and surgical factors (14, 24) also increase the risk of incisional complications or infections. Although no data on the impact of smoking on wound healing after transplantation itself exist, smoking history has been associated with postoperative complications in kidney transplant patients undergoing repair of incisional hernias (25). Risk factors for impaired wound healing that are specific to transplantation include delayed graft function (1, 2, 6), possibly acute rejection (2, 7, 8, 16, 26), and immunosuppression, notably mTOR inhibitor therapy.

MECHANISMS OF WOUND HEALING DISRUPTION BY MTOR INHIBITORS

The process of wound healing involves an initial phase of hemostasis and inflammation, followed by a complex process of cellular proliferation and fibroblast-mediated collagen formation, and finally organization and remodeling of collagen. Any immunosuppressant that interferes with these stages can impair and delay healing. mTOR acts as an important “gatekeeper” for the phosphoinositide 3 kinase/Akt pathway, which is stimulated by interleukin 2 and other cytokines, and influences T-lymphocyte proliferation, expansion, and migration and controls lymphocyte size and metabolic activity (Fig. 1). However, mTOR is also pivotal in many other cellular processes, regulating 1) messenger RNA translation and ribosome biogenesis, 2) cell cycle progression, 3) cellular proliferation and growth, and 4) angiogenesis. By limiting cellular proliferation and angiogenesis of endothelial cells and fibroblasts (27–29), mTOR inhibitors can restrict fibrosis, a key element of successful wound healing. In vitro data in which human lung fibroblasts were exposed to concentrations of various immunosuppressants showed that everolimus and mycophenolate mofetil (MMF) exerted potent antiproliferative effects at concentrations lower than those achieved clinically when used therapeutically, which was not observed with CNIs or corticosteroids (Fig. 2) (27). These results are consistent with animal (29–32) and clinical (33) data showing decreased proliferation of inflammatory cells and myofibroblasts, and inhibition of angiogenesis (34) in the presence of an mTOR inhibitor, resulting in delayed healing and reduced tensile wound strength (30, 35, 36). It has also been proposed that mTOR inhibitors may exert a direct antilymphangiogenic effect (37–39) that could allow lymph fluid to leak from the lymphatic system and predispose patients to the development of lymphocele.

FIGURE 1
FIGURE 1:
The phosphoinositide 3 kinase (PI-3K)/Akt signaling pathway. The mTOR is a gatekeeper molecule for 1) messenger RNA translation and ribosome biogenesis, 2) cell cycle progression, 3) cellular proliferation and growth, and 4) angiogenesis.
FIGURE 2
FIGURE 2:
Absolute [3H]thymidine uptake, a marker of fibroblast proliferation, in cultures of human lung fibroblasts in the presence of starving medium (1% fetal bovine serum [FBS]), growth medium (5% FBS), and immunosuppressive agents at therapeutic serum levels. Values are shown as counts per minute (cpm), mean ± SE. mPred, methylprednisolone; CsA, cyclosporine; Tac, tacrolimus; Aza, azathioprine; MMF, mycophenolate mofetil; EVR, everolimus. Adapted from Azzola et al. (27).

WOUND HEALING COMPLICATIONS IN CLINICAL TRIALS OF MTOR INHIBITORS

Several randomized trials of mTOR inhibitors within various maintenance immunosuppression regimens have described the occurrence of wound healing events in comparison to different control regimens, although in differing levels of detail (Table 1). With the exception of two studies (15, 58), wound healing events have been captured only as part of standard adverse event and serious adverse events reporting and not as a rigid part of the trial documentation and are thus vulnerable to reporting bias. A meta-analysis of studies published up to mid-2005 found a significant increase in the risk of lymphocele in kidney transplant patients given sirolimus or everolimus versus patients receiving CNI therapy or an inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitor (MMF or the antimetabolite prodrug azathioprine) but found no difference in the rate of wound infections (9). The risk of wound complications overall was not reported. A more recent pooled analysis showed a higher incidence of wound complications and lymphocele in kidney transplant patients under mTOR inhibition with either concomitant CNI or mycophenolic acid (MPA) therapy based on trials undertaken since the first introduction of sirolimus (10). Over the 13-year period from which data are available, however, there have been marked changes in mTOR inhibitor dosing regimens. Although variations in reporting criteria mean that comparisons of wound complication rates between studies can only be tentative, the highest incidences of complications reported as adverse events have generally been reported in kidney transplant patients given a loading dose of an mTOR inhibitor with either fixed dosing or concentration-controlled dosing using a high target range (Table 1). Indeed, virtually all studies in which a loading dose of mTOR inhibitor was used have shown a significantly higher rate of wound healing events versus control regimens (Table 1). Fixed-dose mTOR inhibitor regimens per se may not be associated with disruption of healing if dosing is not too high (55, 56) but has generally been replaced by concentration-controlled dosing.

TABLE 1
TABLE 1:
Incidence of wound healing complications in randomized trials of de novo kidney transplant patients receiving a conventional mTOR inhibitor regimen or a control regimen

One of the first studies to use a lower-trough mTOR inhibitor concentration was that of Ciancio et al. (60). In their trial, the target trough level for sirolimus was 8 ng/mL with no loading dose (60). Rates of wound infection or dehiscence were similar using this regimen in combination with either tacrolimus (6%) or cyclosporine (CsA; 4%) compared with tacrolimus-MMF, although the incidence of lymphocele was nonsignificantly higher (Table 2). More recently, two randomized trials of everolimus in kidney transplantation have used today’s standard trough target range of 3 to 8 ng/mL with no loading dose, in combination with low-exposure CsA (57, 58). In the CALLISTO study, the occurrence of wound healing disorders related to the initial transplantation formed part of the primary endpoint of the trial (58, 62). One hundred thirty-nine patients were randomized to start everolimus from the time of transplantation or to receive MPA to week 4, when they were given everolimus. All patients received CsA and steroids. As shown in Figure 3, the rates of wound healing complications at months 1 and 3 were similar in both arms and demonstration a similar duration (mean 43.6 ± 28.2 days with immediate everolimus vs. 56.9 ± 31.8 days, P=0.54). Ultrasound results at week 4 confirmed that there was no difference in perigraft fluid collections (36.7% with de novo everolimus vs. 34.5% with de novo MPA). As well as demonstrating no meaningful difference in early or late wound healing complications between everolimus at standard exposure levels (3–8 ng/mL) and MPA therapy, the CALLISTO study demonstrated that there is no difference between the de novo use of MPA or everolimus with regard to wound healing complications in kidney transplantation.

TABLE 2
TABLE 2:
Incidence of wound healing complications in randomized trials of an mTOR inhibitor in de novo kidney transplant recipients using a modern dosing regimen versus a control regimen
FIGURE 3
FIGURE 3:
Incidence of wound healing complications at months 1 and 3 after kidney transplantation in a randomized trial of patients receiving everolimus from the time of transplant (“de novo everolimus”) or MPA therapy to week 4 converted to everolimus (“de novo MPA”) (CALLISTO) (58). The everolimus C 0 level target range in both treatment arms was 3 to 8 ng/mL. Wound healing complications were defined as superficial or deep fluid collections (hematoma, seroma, or lymphocele), deep or superficial dehiscence, incisional hernia, urine leak, anastomosis disruption, necrosis, or others.

Subsequently, the large A2309 trial examined the occurrence of wound healing with standard-exposure everolimus (3–8 ng/mL) plus reduced-exposure CsA, with no everolimus loading dose, versus MPA and standard-exposure CsA (57). A third treatment arm received everolimus targeting the range 6 to 12 ng/mL. Data at 1 year showed a similar incidence of wound healing complications in patients receiving either standard-exposure everolimus or MPA, including rates of lymphocele (6.6% and 5.1%, respectively), impaired healing (1.8% and 1.1%), and wound dehiscence (1.5% in both groups) (Table 2). Only in the higher everolimus exposure arm did the occurrence of these events exceed the MPA group (57) (Table 1). Using the standard everolimus 3- to 8-ng/mL target range, the rate of lymphocele requiring percutaneous drainage or operative procedure (4.0% and 2.6%, respectively) was identical to that seen in the MPA control arm (2.6% and 2.6%, respectively) (63).

Dose Dependency of mTOR Inhibitor Effect on Wound Healing

An early indication that healing impairment could be minimized by reducing mTOR inhibitor exposure came from a randomized single-center study by Dean et al. (15). In this study, careful reporting of wound disorders revealed a very marked increase in sirolimus-treated patients versus those given tacrolimus (47% vs. 8%, P < 0.001) (15). Both a high loading dose and high trough concentrations of sirolimus were used (15–20 ng/mL). Part-way through the study, however, the sirolimus trough target level was reduced to 10 to 15 ng/mL and the rate of wound healing complications fell from 55% to 35%, although patients with a BMI greater than 32 kg/m2 were excluded at the same time so the improvement could not be solely attributed to the effect of sirolimus reduction. An initiative to reduce wound healing complications at the Cleveland Clinic included discontinuation of a loading dose of sirolimus and modifications of the surgical technique and exclusion of patients with a BMI greater than 32 kg/m2 (2). In this consecutive series of 307 patients, these changes were found retrospectively to result in a significant decrease in wound problems (7.9% of patients vs. 19.6% previously, P=0.007) and surgically managed lymphocele (4.8% vs. 24.5%, P < 0.001).

In studies that have reported wound healing events for two different mTOR inhibitor dosing regimens, results have uniformly shown a numerically lower incidence of events in the reduced exposure group (41, 43, 44, 55, 56, 63, 65), regardless of whether fixed dosing or concentration-controlled dosing was used (Tables 1 and 3). This dose dependency remains apparent with modern regimens in which loading doses are avoided and lower trough concentration targets are used than in the past (50, 64).

TABLE 3
TABLE 3:
Incidence of wound healing complications in randomized trials comparing two mTOR exposure ranges within a modern regimen

In a post hoc exposure-response analysis, patients in the highest quartile of everolimus time-normalized concentrations in the A2309 study demonstrated a higher incidence of wound healing complications (43.9%) than patients did within the standard 3- to 8-ng/mL target range (26%) (63). An effect on wound healing, however, does not seem to be entirely avoided even in the presence of reduced mTOR inhibitor exposure. In the SYMPHONY study, a regimen of low-exposure sirolimus (4–8 ng/mL) with MMF and steroids was still associated with a greater frequency of delayed wound healing and, particularly, lymphocele compared with non–mTOR inhibitor regimens (61) (Table 2). Patients randomized to the low-exposure sirolimus arm also experienced a higher rate of acute rejection and required more steroid therapy. The frequency of wound healing complications was not unexpected because the de novo combination of an mTOR inhibitor and an IMPDH inhibitor, both potent inhibitors of fibroblast proliferation (27), is likely to be particularly unfavorable and should be avoided (see Effect of Concomitant Immunosuppression – Mycophenolic Acid section).

Effect of Obesity

As might be expected, obesity has been shown to be an independent risk factor for impaired wound healing in patients receiving an mTOR inhibitor. Two retrospective analyses in sirolimus-treated populations have reported a BMI greater than 30 kg/m2 to be associated with an increased risk of wound complications including (3) or excluding (8) wound infections. In their prospective randomized trial of high-dose sirolimus versus tacrolimus in which wound healing events were meticulously recorded, Dean et al. (15) demonstrated a dramatic increase in the rate of wound complications with rising BMI in the sirolimus arm that was largely absent in tacrolimus-treated patients. The combination of mTOR inhibition and obesity was highlighted in the recent A2309 study, in which patients with a BMI above the 75th percentile (≥29 kg/m2) showed more frequent wound healing events in the everolimus 3- to 8- and 6- to 12-ng/mL arms (46% and 50%, respectively) compared with MMF (27%, P < 0.05) (57).

EFFECT OF CONCOMITANT IMMUNOSUPPRESSION

Mycophenolic Acid

IMPDH inhibitors, such as MPA, are potent inhibitors of fibroblast proliferation at lower concentrations than are used clinically (Fig. 2) (27), although an IMPDH-independent effect on wound healing has also been postulated (66). Accordingly, concomitant use of MPA with an mTOR inhibitor may potentiate the risk of wound healing disturbances.

Examination of data from trials in which sirolimus and MPA therapy were used concomitantly (15, 44, 48, 54, 61) raises potential concerns about the concomitant use of MPA with mTOR inhibition in wound healing (Tables 1 and 2). It can be difficult to disentangle the effect of mTOR inhibitor exposure to that of coadministration of MPA because, generally, the two classes of drugs are used together only within CNI-free regimens using high exposure levels for the mTOR inhibitor (15, 44, 54). Büchler et al. (48) described a significantly higher rate of incisional hernias or wound dehiscence in patients given a high loading dose of sirolimus with MMF compared with a standard regimen of CsA and MMF, whereas Pescovitz et al. (54) observed a twofold higher rate of incision site complications with high-exposure sirolimus-MMF versus CsA-MMF (Table 1). In the recent SYMPHONY trial, however, patients receiving a combination of sirolimus and MMF from the time of kidney transplantation experienced a higher rate of lymphocele versus patients receiving CNI-based immunosuppression despite only low (4–8 ng/mL) exposure to sirolimus and no loading dose (15.8% vs. 4.0%–7.0%, P < 0.001) (61). In the ORION study, sirolimus-MPA was associated with a slightly higher rate of delayed wound healing and lymphocele compared with sirolimus-tacrolimus, but the difference was not marked and sirolimus target ranges differed between groups (Table 1) (44). No definitive conclusions can be drawn about a possible additive effect of mTOR inhibition and MPA based on the current data, but it is interesting to note that a recent meta-analysis observed a higher relative risk of wound healing complications for kidney transplant patients receiving an mTOR inhibitor with MPA (odds ratio, 3.00; 95% CI, 1.61–5.59) than with CNI therapy (odds ratio, 1.777; 95% CI, 1.31–2.37) (10).

Steroids

Experimental evidence has suggested that steroids could influence wound healing by restricting the activity of inflammatory cells and fibroblasts and delaying deposition of collagen and other healing mechanisms (67, 68). In a rat model, addition of steroids to sirolimus prolonged abdominal wound healing, profoundly so in animals receiving high-dose steroids (69). Evidence stating that steroid administration per se is an independent risk factor for impaired wound healing in kidney transplant patients is lacking, although its use has been associated with wound complications after cesarean delivery (59), pancreaticoduodenectomy (70), and diagnostic skin biopsies (71). It seems possible that concomitant use of sirolimus and steroids will be unfavorable. A prospective analysis of 148 sirolimus-treated kidney transplant patients undergoing early (day 5) or late (month 6) steroid withdrawal found the incidence of wound complications (dehiscence, leakage, hematoma, seroma, or lymphocele) to be significantly lower in the early steroid-withdrawal group (18.8% vs. 45.6%), with the variation largely accounted for by differences in the rates of dehiscence and lymphocele (72). Multivariate analysis showed that the use of steroids with sirolimus maintenance therapy increased the risk of wound complications by 4.2-fold. A pooled analysis of data on the rate of lymphocele, specifically, found that early steroid withdrawal was associated with a reduced rate of lymphocele in patients receiving continuing low-dose steroids or with late steroid withdrawal (10). This effect is not confirmed, however, or may be small (73, 74). In a randomized trial in which 150 kidney transplant patients receiving tacrolimus with either sirolimus or MMF—both in steroid-free regimens—the overall rate of wound healing was similar in both groups (6.7% with sirolimus and 4.0% with MMF), as was the incidence of both wound infection (2.7% vs. 4.0%) and lymphocele (2.6% vs. 1.3%) (74).

IMPLICATIONS FOR DE NOVO USE OF MTOR INHIBITION IN KIDNEY TRANSPLANT RECIPIENTS

Historical concerns about impaired healing seem to be less relevant using modern mTOR inhibitor regimens, but an increased risk remains when loading doses are used or exposure to mTOR inhibitors is high. A recent large-scale study confirmed that use of a loading dose is not required if induction therapy is given: good efficacy was achieved using everolimus at standard exposure levels with low-dose CsA and steroids and no loading dose (64). A starting dose of 2 to 4 mg/d for sirolimus (75) and 1.5 mg/d for everolimus (64) is appropriate, increased only if target levels are not achieved by day 7. Delaying introduction of mTOR inhibitors does not seem to affect the risk of wound healing complications (58).

High sirolimus exposure levels (>12 ng/mL) have typically been used in entirely CNI-free regimens (44, 54)—a strategy that has proved unfavorable in preventing rejection and wound healing complications (44, 54, 76). Target ranges of 5 to 10 ng/mL for sirolimus (76) and 3 to 8 ng/mL for everolimus (57) are recommended, with induction therapy and low CNI exposure, unless additional immunosuppression is considered necessary in the case of patients at high immunologic risk. High-exposure mTOR inhibition should be avoided, particularly in obese patients.

It is possible that the combination of mTOR and IMPDH inhibition by MPA may be detrimental to healing, as suggested by results from the SYMPHONY study (61, 77), and although this remains speculative, it may be advisable to avoid combined therapy with an mTOR inhibitor and MPA in the early period after kidney transplantation. Although the combination of sirolimus and steroids may disrupt the healing process, CNI-free and steroid-free mTOR inhibitor–based immunosuppression is problematic (75, 78) and unlikely to become widely used.

MTOR INHIBITION AND ELECTIVE SURGERY IN TRANSPLANT RECIPIENTS

There are no robust data available concerning the influence of mTOR inhibitors on wound healing after elective surgical procedures in transplant recipients. Any such analysis would need to take into account the generally inferior healing rates observed in immunosuppressed transplant recipients. In one series of 40 diabetic kidney transplant patients not receiving an mTOR inhibitor, for example, healing of foot ulcers was markedly worse than in nontransplanted controls (79). The literature contains only uncontrolled single-center reports of interruption or withdrawal of mTOR inhibitors before surgical reintervention relating to the transplant incision (80), case studies in which mTOR inhibitor was continued successfully during elective surgery after transplant (81), and reports of an effect on gastrointestinal ulceration and healing (82–84) in solid organ transplant recipients. Thus, no firm conclusions can be drawn regarding the advisability of withdrawing mTOR inhibitors before elective surgery in transplant recipients. Clearly, any alteration to the immunosuppressive regimen would have to take into account a potential risk of late rejection.

In the absence of robust data, an individualized approach based on clinical experience is necessary. It is standard practice to reduce exposure to any type of proliferation inhibitor if major surgery is planned in transplant recipients. Empirically, it would seem reasonable to consider interrupting high-exposure mTOR inhibitor exposure for 2 to 4 months before elective surgery in transplant recipients but to continue low-exposure mTOR inhibitor exposure unchanged. In the event of urgent surgery, severe open wound complications, or urinary fistulas, the increased risk of impaired wound healing due to concomitant risk factors could justify withdrawal of mTOR inhibition.

CONCLUSIONS

Wound complications, although rarely affecting graft or patient survival, can incur considerable morbidity, prolong hospital stay, and risk the need for surgical reintervention, with an associated increase in costs. They can be attributed to a variety of factors, including surgical experience, comorbidities, and lifestyle issues. Randomized studies exploring immunosuppressive regimens are the largest source of data, although reporting is generally linked to adverse events and serious adverse events rather than focusing specifically on defined wound healing endpoints. This overview demonstrates that there has been a learning curve in the use of mTOR inhibitors since their introduction. Numerical differences in the incidence of wound complications between high- and low-exposure mTOR inhibitor regimens point to benefits from a low-exposure approach, but no statistical analyses are available because no study using different levels of exposure has used wound healing as a primary endpoint. With current knowledge, undertaking such a study may now be considered unethical. Nevertheless, after a shift from high-exposure regimens with a high rate of wound healing complications, there is little convincing evidence that low-exposure mTOR regimens without a loading dose, given with low-exposure CNI instead of MPA, induce markedly more wound healing problems than a CNI-MPA regimen (58, 62). However, there are indicators that obesity might influence wound healing in patients treated with mTOR inhibitors, and until more data are available, it would seem prudent to avoid mTOR inhibition in patients with a BMI greater than 32 kg/m2 based on limited clinical experience to date (2, 15). With the range 29 to 32 kg/m2, an individualized approach to use of mTOR inhibitors could be adopted. Meticulous surgical technique, a cautious use of mTOR inhibitors in obese patients, and avoidance of high exposure to mTOR inhibitors, coupled with close monitoring, can ensure that wound healing disorders remain infrequent and do not disrupt the patient’s recovery. Studies of mTOR inhibition undertaken from a surgical viewpoint, which focus on wound healing issues with a strict reporting methodology, are warranted to achieve a final evidence-based conclusion.

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Keywords:

Wound; Healing; Kidney transplantation; Sirolimus; Everolimus

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