Journal Logo

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

Author Information
doi: 10.1097/TP.0b013e3182551021
  • Free
  • Video


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.


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.


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.


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.

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.
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).


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.

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.

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
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).

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).


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).


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).


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.


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.


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.


1. Flechner SM, Zhou L, Derweesh I, et al.. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation 2003; 76: 1729.
2. Tiong HY, Flechner SM, Zhou L, et al.. A systematic approach to minimizing wound problems for de novo sirolimus-treated kidney transplant recipients. Transplantation 2009; 87: 296.
3. Knight RJ, Villa M, Laskey R, et al.. Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients. Clin Transplant 2007; 21: 460.
4. Kuo JH, Wong MS, Perez RV, et al.. Renal transplant wound complications in the modern era of obesity. J Surg Res 2012; 173: 216.
5. Mehrabi A, Fonouni H, Wente M, et al.. Wound complications following kidney and liver transplantation. Clin Transplant 2006; 20 (suppl 17): 97.
6. Kiberd B, Panek R, Clase CM, et al.. The morbidity of prolonged wound drainage after kidney transplantation. J Urol 1999; 161: 1467.
7. Humar A, Ramcharan T, Denny R, et al.. Are wound complications after a kidney transplant more common with modern immunosuppression? Transplantation 2001; 72: 1920.
8. Grim SA, Slover CM, Sankary H, et al.. Risk factors for wound healing complications in sirolimus-treated renal transplant recipients. Transplant Proc 2006; 38: 3520.
9. Webster AC, Lee VW, Chapman JR, et al.. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006; 81: 1234.
10. Pengel LH, Liu LQ, Morris PJ. Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials. Transpl Int 2011; 12: 1216.
11. Valente JF, Hricik D, Weigel K, et al.. Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003; 3: 1128.
12. Merion RM, Twork AM, Rosenberg L, et al.. Obesity and renal transplantation. Surg Gynecol Obstet 1991; 172: 367.
13. Pérez-Sáez MJ, Toledo K, Navarro MD, et al.. Long-term survival of simultaneous pancreas-kidney transplantation: influence of early posttransplantation complications. Transplant Proc 2011; 43: 2160.
14. Seow YY, Alkari B, Dyer P, et al.. Cold ischemia time, surgeon, time of day, and surgical complications. Transplantation 2004; 77: 1386.
15. Dean PG, Lund WJ, Larson TS, et al.. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 2004; 77: 1555.
16. Goel M, Flechner SM, Zhou L, et al.. The influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation. J Urol 2004; 171: 1788.
17. Johnson DW, Isbel NM, Brown AM, et al.. The effect of obesity on renal transplant outcomes. Transplantation 2002; 74: 675.
18. Sørensen LT, Hemmingsen U, Kallehave F, et al.. Risk factors for tissue and wound complications in gastrointestinal surgery. Ann Surg 2005; 241: 654.
19. Piffaretti G, Mariscalco G, Tozzi M, et al.. Predictive factors of complications after surgical repair of iatrogenic femoral pseudoaneurysms. World J Surg 2011; 35: 911.
20. Riou JP, Cohen JR, Johnson H Jr. Factors influencing wound dehiscence. Am J Surg 1992; 163: 324.
21. Matsuda K, Hotta T, Takifuji K, et al.. Long-term comorbidity of diabetes mellitus is a risk factor for perineal wound complications after an abdominoperineal resection. Langenbecks Arch Surg 2009; 394: 65.
22. Karthikesalingam A, Kitcat M, Malata CM. Abdominoplasty in patients with and without pre-existing scars: a retrospective comparison. J Plast Reconstr Aesthet Surg 2011; 64: 369.
23. Douzdjian V, Gugliuzza KK. The impact of midline versus transverse incisions on wound complications and outcome in simultaneous pancreas-kidney transplants: a retrospective analysis. Transpl Int 1996; 9: 62.
24. Nanni G, Tondolo V, Citterio F, et al.. Comparison of oblique versus hockey-stick surgical incision for kidney transplantation. Transplant Proc 2005; 37: 2479.
25. Chang EI, Galvez MG, Padilla BE, et al.. Ten-year retrospective analysis of incisional herniorrhaphy following renal transplantation. Arch Surg 2011; 146: 21.
26. Khauli RB, Stoff JS, Lovewell T, et al.. Post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management. J Urol 1993; 150: 22.
27. Azzola A, Havryk A, Chhajed P, et al.. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation 2004; 77: 275.
28. Akselband Y, Harding MW, Nelson PA. Rapamycin inhibits spontaneous and fibroblast growth factor beta–stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc 1991; 23: 2833.
29. Humar R, Kiefer FN, Berns H, et al.. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 2002; 16: 771.
30. Ekici Y, Emiroglu R, Ozdemir H, et al.. Effect of rapamycin on wound healing: an experimental study. Transplant Proc 2007; 39: 1201.
31. Simler NR, Howell DCJ, Marshall RP, et al.. The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur Resp J 2002; 19: 1124.
32. Maasilta PK, Salminen US, Lautenschlager IT, et al.. Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis. Transplantation 2001: 72: 998.
33. Nair RV, Huang X, Shorthouse R, et al.. Antiproliferative effect of rapamycin on growth factor–stimulated human adult lung fibroblasts in vitro may explain its superior efficacy for prevention and treatment of allograft obliterative airway disease in vivo. Transplant Proc 1997; 29: 614.
34. Guba M, von Breitenbuch P, Steinbauer M, et al.. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128.
35. van der Vliet JA, Willems MC, de Man BM, et al.. Everolimus interferes with healing of experimental intestinal anastomoses. Transplantation 2006; 82: 1477.
36. Willems MC, van der Vliet JA, de Man BM, et al.. Persistent effects of everolimus on strength of experimental wounds in intestine and fascia. Wound Repair Regen 2010; 18: 98.
37. Huber S, Bruns CJ, Schmid G, et al.. Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney Int 2007; 71: 771.
38. Patel V, Marsh CA, Dorsam RT, et al.. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Res 2011; 71: 7103.
39. Kobayashi S, Kishimoto T, Kamata S, et al.. Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci 2007; 98: 726.
40. Sampaio EL, Pinheiro-Machado PG, Garcia R, et al.. Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen. Clin Transplant 2008; 22: 141.
41. Vitko S, Wlodarczyk Z, Kyllönen L, et al.. Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study. Am J Transplant 2006; 6: 531.
42. Machado PG, Felipe CR, Hanzawa NM, et al.. An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination. Clin Transplant 2004; 18: 28.
43. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356: 195.
44. Flechner SM, Glyda M, Cockfield S, et al.. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant 2011; 11: 1633.
45. Franz S, Regeniter A, Hopfer H, et al.. Tubular toxicity in sirolimus- and cyclosporine-based transplant immunosuppression strategies: an ancillary study from a randomized controlled trial. Am J Kidney Dis 2010; 55: 335.
46. Glotz D, Charpentier B, Abramovicz D, et al.. Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids. Transplantation 2010; 89: 1511.
47. Durrbach A, Rostaing L, Tricot L, et al.. Prospective comparison of the use of sirolimus and cyclosporine in recipients of a kidney from an expanded criteria donor. Transplantation 2008; 85: 486.
48. Büchler M, Caillard S, Barbier S, et al.. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am J Transplant 2007; 7: 2522.
49. Martinez-Mier G, Mendez-Lopez MT, Budar-Fernandez LF, et al.. Living related kidney transplantation without calcineurin inhibitors: initial experience in a Mexican center. Transplantation 2006; 82: 1533.
50. Kandaswamy R, Melancon JK, Dunn T, et al.. A prospective randomized trial of steroid-free maintenance regimens in kidney transplant recipients—an interim analysis. Am J Transplant 2005; 5: 1529.
51. Kreis H, Cisterne JM, Land W, et al.. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252.
52. Flechner SM, Goldfarb D, Modlin C, et al.. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002; 74: 1070.
53. Groth CG, Bäckman L, Morales JM, et al.. Sirolimus (rapamycin)–based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036.
54. Pescovitz MD, Vincenti F, Hart M, et al.. Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients. Br J Clin Pharmacol 2007; 64: 758.
55. Vítko S, Margreiter R, Weimar W, et al.. Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 2005; 78: 1532.
56. Lorber MI, Mulgaonkar S, Butt KM, et al.. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation 2005; 80: 244.
57. Tedesco Silva H Jr, Cibrik D, Johnston T, et al.. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant 2010; 10: 1401.
58. Albano L, Berthoux F, Moal MC, et al.. Incidence of delayed graft function and wound healing complications after deceased-donor kidney transplantation is not affected by de novo everolimus. Transplantation 2009; 88: 69.
59. De Vivo A, Mancuso A, Giabcobbe A, et al.. Wound length and corticosteroid administration as risk factors for surgical-site complications following lymphocele section. Acta Obstet Gynecol Scand 2010; 89: 355.
60. Ciancio G, Burke GW, Gaynor JJ, et al.. A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 2004; 77: 252.
61. Ekberg H, Bernasconi C, Nöldeke J, et al.. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the SYMPHONY study. Nephrol Dial Transplant 2010; 25: 2004.
62. Dantal J, Berthoux F, Moal MC, et al.. Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial. Transpl Int 2010; 23: 1084.
63. Center for Drug Evaluation and Research. Application number 21-560x000. Medical Reviews. Available at: Accessed December 2011.
64. Salvadori M, Scolari MP, Bertoni E, et al.. Everolimus with very low-exposure cyclosporine A in de novo kidney transplantation: a multicenter, randomized, controlled trial. Transplantation 2009: 88: 1194.
65. Vitko S, Tedesco H, Eris J, et al.. Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004; 4: 626.
66. Petrova DT, Brandhorst G, Brehmer F, et al.. Mycophenolic acid displays IMPDH-dependent and IMPDH-independent effects on renal fibroblast proliferation and function. Ther Drug Monit 2010; 32: 405.
67. Wicke C, Halliday B, Allen D, et al.. Effects of steroids and retinoids on wound healing. Arch Surg 2000; 135: 1265.
68. Anstead GM. Steroids, retinoids, and wound healing. Adv Wound Care 1998; 11: 277.
69. Gaber MW, Aziz AM, Shang X, et al.. Changes in abdominal wounds following treatment with sirolimus and steroids in a rat model. Transplant Proc 2006; 38: 3331.
70. Greenblatt DY, Kelly KJ, Rajamanickam V, et al.. Preoperative factors predict perioperative morbidity and mortality after pancreaticoduodenectomy. Ann Surg Oncol 2011; 18: 2126.
71. Wahie S, Lawrence CM. Wound complications following diagnostic skin biopsies in dermatology inpatients. Arch Dermatol 2007; 143: 1267.
72. Sandrini S, Setti G, Bossini N, et al.. Steroid withdrawal five days after renal transplantation allows for the prevention of wound-healing complications associated with sirolimus therapy. Clin Transplant 2009; 23: 16.
73. Montagnino G, Sandrini S, Iorio B, et al.. A randomized exploratory trial of steroid avoidance in renal transplant patients treated with everolimus and low-dose cyclosporine. Nephrol Dial Transplant 2008; 23: 707.
74. Kumar MSA, Heifets M, Fyfe B, et al.. Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy. Transplantation 2005; 80: 807.
75. Campistol JM, Cockwell P, Diekmann F, et al.. Practical recommendations for the early use of mTOR inhibitors (sirolimus) in renal transplantation. Transplant Int 2009; 22: 681.
76. Smith MP, Newstead CG, Ahmad N, et al.. Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. Transplantation 2008; 85: 636.
77. Ekberg H, Tedesco-Silva H, Demirbas A, et al.. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562.
78. Matas AJ. Resolved: in minimizing kidney transplant immunosuppression, steroids should go before calcineurin inhibitors: pro. J Am Soc Nephrol 2007; 18: 3026.
79. Fletcher F, Ain M, Jacobs R. Healing of foot ulcers in immunosuppressed renal transplant patients. Clin Orthop Relat Res 1993; (296): 37.
80. Scheuerlein H, Rauchfuss F, Gharbi A, et al.. Laparoscopic incisional hernia repair after solid-organ transplantation. Transplant Proc 2011; 43: 1783.
81. Pascual J, Galeano C, Celemín D, et al.. Uneventful thoracic healing with everolimus after aortic valve replacement. Ann Thorac Surg 2007; 84: 271.
82. Altomare JF, Smith RE, Potdar S, et al.. Delayed gastric ulcer healing associated with sirolimus. Transplantation 2006; 82: 437.
83. Molinari M, Al-Saif F, Ryan EA, et al.. Sirolimus-induced ulceration of the small bowel in islet transplant recipients: report of two cases. Am J Transplant 2005; 5: 2799.
84. Smith AD, Bai D, Marroquin CE, et al.. Gastrointestinal hemorrhage due to complicated gastroduodenal ulcer disease in liver transplant patients taking sirolimus. Clin Transplant 2005; 19: 250.

Wound; Healing; Kidney transplantation; Sirolimus; Everolimus

© 2012 Lippincott Williams & Wilkins, Inc.