To show the effects of MPA on human fibroblast proliferation, migration, and adhesion in vitro and in vivo and its implication on wound healing
Human fibroblast was cultured. Expression of cytoskeletal proteins vinculin, actin, and tubulin in fibroblasts was assessed by polymerase chain reaction (PCR) and western blot. RNA and protein content and its effect on rearrangement on cytoskeleton was assessed by immunofluorescence. Scratch test was done to assess reduced migration activity. The results of the cultured human fibroblasts were applied to skin biopsies of renal transplant recipients. Skin biopsies of patients treated with MPA were assessed with control.
The authors showed a downregulation of the cytoskeletal proteins vinculin, actin, and tubulin in fibroblasts exposed to pharmacological doses of MPA. This reduction in RNA and protein content is accompanied by a substantial rearrangement of the cytoskeleton in MPA-treated fibroblasts. The dysfunctional fibroblast growth was validated by scratch test documenting impaired migrational capacity. In contrast, cell adhesion was increased in MPA-treated fibroblasts. The results of the cultured human fibroblasts were applied to skin biopsies of renal transplant recipients. Skin biopsies of patients treated with MPA expressed less vinculin, actin, and tubulin as compared to control biopsies.
To study the effect of MMF on wound healing in rodent model
4 groups were made from ninety-six male Wistar rats. All the groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. 4th group started the medication 3 days after the laparotomy and was analyzed after 7 days. Half of the 4th group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured by assessing bursting pressure, breaking strength, and histology.
On day 3, it was shown that there was stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength were higher in the low-dose and high-dose MMF group compared with the control group. However, wound strength in abdominal wound was less in the highest MMF group.
To study the synthesis of type I (mature) and type III (immature) collagen in bladder suture of rats treated with a combination of TAC and MMF for 15 days.
Thirty rats were grouped into 3 groups: the sham (did not receive any treatment), control (saline solution), and experimental groups (received 0.1 mg/kg/day of TAC with 20 mg/kg/day of MMF). All treatments were given for 15 days. All the animals underwent laparotomy, cystotomy, and bladder suture in two planes with surgical PDS 5–0 thread. The surgical specimens of the bladder suture area were assessed for the type of collagen deposition.
Type I collagen production and deposition in the sham and control groups were more as compared to the experimental group. TAC and MMF change qualitatively to collagen type III in wound
To study the effect of MMF on proximal convoluted tubules (PCT) and distal convoluted tubules (DCT).
Human PTC and DTC were cultured in the presence of different concentrations of MPA (0.25–50 microM) or MPA plus guanosine (100 microM). Cells were stimulated by a combination of cytokines. Secretion of RANTES protein was evaluated. Cell surface expression of HLA-DR and ICAM-1.
MPA inhibited cell growth of PTC and DTC in a dose-dependent manner. This effect was totally abolished by the addition of guanosine.
To study effects of MPA human mesangial cells (HMC) activation.
Primary cultures of HMC and of an immortalized HMC clone were stimulated and treated by MPA at clinically relevant concentrations (1 to 10 mol/L) for 24 hours.
Treatment of cultured HMC with MPA inhibited mesangial cell proliferation and matrix production.
To study the effect of mesangial cell (MC) proliferation in inflammatory proliferative glomerular diseases.
The growth of fetal rat and human MCs were arrested by taking out fetal calf serum (FCS) and then stimulated by addition of FCS, platelet-derived growth factor (PDGF), or lysophosphatidic acid. Different concentrations of MMF (0.019–10 microM) were added concomitantly in the presence or absence of guanosine.
MMF inhibited mitogen-induced human rat MC proliferation. The effect on human MC was more pronounced.
To investigate the effect of MMF on whether it reduces interstitial myofibroblast infiltration.
Forty-five rats underwent renal ablation. One group received daily dose of vehicle (N 5/20). The other group received MMF (N 5/25). This was continued during the 60 days following surgery.
Cellular proliferation in renal tubules, interestitium, and glomeruli along with myofibroblast infiltration in interestitium and interstitial type III collagen deposition were significantly reduced by MMF treatment. MPA showed a dose-dependent inhibitory effect on in vitro proliferation of rat fibroblasts. MMF treatment improved renal function and resulted in reduced kidney hypertrophy and glomerular volume parameters and progressively decreased remnant kidney hypertrophy and glomerular volume increment.
The objective of the study was to avoid the nephrotoxic effects by CsA avoidance using MMF during induction and maintenance.
In primary CsA, free induction methyl prednisolone and ATG were given during induction and oral MMF 1 gram twice a day was given within 24 hours after surgery. In late group, CsA was withdrawn after 4 weeks slowly (25 mg/day) and was kept on MMF.
Wound healing complications occurred in 16.6% of MMF treated patients.
Retrospective study to assess MMF on wound healing and lymphocele formation.
Retrospective single-center analysis of 144 patients receiving a CsA-based immunosuppression with prednisolone (Pred) and either MMF (n = 77) or AZA (AZA, n = 77) was done. The end points were lymphocele and nonprimary wound healing during 6 months follow-up.
More lymphoceles were observed in MMF group (OR = 2.6; = 0.03). More fluid drainage (17 vs. 5 interventions) and sclerotherapies (8 vs. 0) were done in MMF group.
Retrospective analysis of effect of SRL vs. MMF on surgical complications and wound healing in adult kidney transplant recipients.
Patients on MMF and SRL were retrospectively analyzed for wound healing complication via logistic regression analysis.
The incidence of wound complications was statistically different for patients receiving MMF compared to SRL: 2.4% for group 1 vs. 43.2% for group 2 ( < 0.0001).
This prospective randomized study was done to compare the safety and efficacy of an SRL-MMF-based regimen with a CsA -MMF-based regimen after induction therapy with polyclonal antilymphocyte antibodies, with withdrawal of steroids 6 months.
Primary end point was graft function at 12 months. Secondary outcome included acute rejection, delayed graft function, slow graft function, and CMV infection.
Hernial eventration/wound evisceration was in 7/71 in SRL-MMF group as compared to 0/71 in CsA-MMF group
To assess safety and efficacy of two SRL, dosing regimens were compared with TAC and MMF (ORION study)
Patients were randomized to group 1 (SRL + TAC); week 13 TAC elimination, group 2 (SRL + MMF), or group 3 (TAC + MMF)).
Delayed wound healing was present in 16.4% (SRL-TAC elimination group) and 23% (SRL + MMF) with < 0.05 between the two groups. Lymphocele was present in 18.4% in SRL-MMF group.
To assess adverse events in kidney transplant recipient who received different immunosuppressive
Kidney transplant recipient undergoing kidney transplant received low-dose SRL or CsA (TAC or SRL) in addition to daclizumab induction or standard-dose CsA without induction. All patients received MMF and corticosteroids.
17% patients have delayed wound healing in low-dose SRL and MMF and was significant as compared to another group with value = 0.006. The incidence of lymphocele was 15.8% in low-dose SRL-MMF and was significant as compared to other groups with value < 0.001.
Pengel LH et al. [SRL 16]
Transpl Int/2011
To do metanalysis to assess if wound complications or lymphoceles occur more often in solid-organ transplant recipients on mTOR inhibitors.
Metanalysis of 17 randomized control trials was done.
Incidence of wound healing complications (OR 3.00, CI 1.61–5.59) and lymphocele (OR 2.13, CI 1.57–2.90) were significantly higher in mTOR-I and MMF as compared to mTOR-I and calcineurin inhibitor where incidence of wound healing complications was (OR 1.77, CI 1.31–2.37) and that of lymphoceles (OR 2.07, CI 1.62–2.65) [17].
