2021, Number 4
<< Back Next >>
Rev Nefrol Dial Traspl 2021; 41 (4)
The effects of tacrolimus and mycophenolate mofetil on regression of encapsulating peritoneal sclerosis in a rat model
Huddam B, Sasmaz S, Haberal N, Azak A, Gibyeli GD, Kocak G, Karakus V, Alp A, Duranay M
Language: English
References: 27
Page: 264-274
PDF size: 566.60 Kb.
ABSTRACT
Objective: Encapsulating peritoneal
sclerosis (EPS) is a rare, but potentially
fatal complication of peritoneal
dialysis. Currently, treatment of
peritoneal fibrosis is not fully possible
yet. In this study, we aimed to
demonstrate the effects of tacrolimus
therapy on peritoneal fibrosis and
inflammation when administered
alone or with mycophenolate
mofetil (MMF) in the EPS model
induced in rats.
Methods: Thirty
six Wistar albino rats were separated
into six equal groups. Group I was
the control group. Group II-VI
were administered intraperitoneal
chlorhexidine (CH) for induced
EPS model in rats. Group II, IV,
V, VI were administered isotonic
liquid, tacrolimus, tacrolimus and
concurrently with CH, tacrolimus
and MMF together, respectively.
Group III was not administered any
drug. All peritoneal samples were
stained immunohistochemically
with matrix metalloproteinase-2
(MMP-2) antibody. Thickness of
peritoneal fibrosis, subserosal large
collagen fibers, subserosal fibroblast
proliferation and subserosal
fibrotic matrix deposition were
Results: Comparing the
experimentally induced EPS groups,
the best histopathological results and
the largest staining with MMP-2 were
achieved in Group VI. Furthermore,
in all treatment groups (IV, V, VI)
more staining with MMP-2 was
detected compared to non-treatment
groups (I, II, III) but no statistically
significant differences were found
among all groups. A statistically
significant remission was observed
in all histopathological parameters,
primarily peritoneal thickness in
rats that were administered MMF
with tacrolimus, compared to rats
which were administered tacrolimus
only.
Conclusion: Concurrent use
of tacrolimus and MMF in the
treatment of EPS may be a promising
approach.
REFERENCES
Krediet RT. 30 years of peritoneal dialysis development:the past and the future. Perit Dial Int. 2007;27 (Suppl2.:S35-41.
Hirahara I, Inoue M, Okuda K, Ando Y, Muto S,Kusano E. The potential of matrix metalloproteinase-2as a marker of peritoneal injury, increased solutetransport, or progression to encapsulating peritonealsclerosis during peritoneal dialysis: a multicentre studyin Japan. Nephrol Dial Transplant. 2007;22(2):560-7.doi: 10.1093/ndt/gfl566.
Hung KY, Huang JW, Tsai TJ, Hsieh BS. Peritonealfibrosing syndrome: pathogenetic mechanismand current therapeutic strategies. J Chin MedAssoc. 2005;68(9):401-5. doi: 10.1016/S1726-4901(09)70154-6.
Martin J, Yung S, Robson RL, Steadman R, Davies M.Production and regulation of matrix metalloproteinasesand their inhibitors by human peritoneal mesothelialcells. Perit Dial Int. 2000;20(5):524-33.
Fukudome K, Fujimoto S, Sato Y, Hisanaga S, EtoT. Peritonitis increases MMP-9 activity in peritonealeffluent from CAPD patients. Nephron. 2001;87(1):35-41. doi: 10.1159/000045882.
Nghiem P. “Topical immunomodulators?”:introducing old friends and a new ally, tacrolimus. JAm Acad Dermatol. 2001;44(1):111-3. doi: 10.1067/mjd.2001.110902.
Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, CejalvoD. Neutrophil infiltration as an important factor inliver ischemia and reperfusion injury. Modulatingeffects of FK506 and cyclosporine. Transplantation.1993;55(6):1265-72. doi: 10.1097/00007890-199306000-00011.
Anglicheau D, Legendre C, Beaune P, ThervetE. Cytochrome P450 3A polymorphisms andimmunosuppressive drugs: an update. Pharmacogenomics.2007;8(7):835-49. doi: 10.2217/14622416.8.7.835.
Nagano J, Iyonaga K, Kawamura K, Yamashita A,Ichiyasu H, Okamoto T, et al. Use of tacrolimus,a potent antifibrotic agent, in bleomycin-inducedlung fibrosis. Eur Respir J. 2006;27(3):460-9. doi:10.1183/09031936.06.00070705.
Khanna A, Plummer M, Bromberek C, BresnahanB, Hariharan S. Expression of TGF-beta andfibrogenic genes in transplant recipients withtacrolimus and cyclosporine nephrotoxicity. KidneyInt. 2002;62(6):2257-63. doi: 10.1046/j.1523-1755.2002.00668.x.
Bicknell GR, Williams ST, Shaw JA, Pringle JH,Furness PN, Nicholson ML. Differential effects ofcyclosporin and tacrolimus on the expression offibrosis-associated genes in isolated glomeruli fromrenal transplants. Br J Surg. 2000;87(11):1569-75. doi:10.1046/j.1365-2168.2000.01577.x.
Hur E, Bozkurt D, Timur O, Bicak S, Sarsik B,Akcicek F, et al. The effects of mycophenolate mofetilon encapsulated peritoneal sclerosis model in rats. ClinNephrol. 2012;77(1):1-7. doi: 10.5414/cn107140.
Huddam B, Başaran M, Koçak G, Azak A, Yalçın F,Reyhan NH, et al. The use of mycophenolate mofetilin experimental encapsulating peritoneal sclerosis.Int Urol Nephrol. 2015;47(8):1423-8. doi: 10.1007/s11255-015-1015-z.
Lafrance JP, Létourneau I, Ouimet D, BonnardeauxA, Leblanc M, Mathieu N, et al. Successfultreatment of encapsulating peritoneal sclerosis withimmunosuppressive therapy. Am J Kidney Dis.2008;51(2):e7-10. doi: 10.1053/j.ajkd.2007.07.036.
Jiang S, Tang Q, Rong R, Tang L, Xu M, Lu J, etal. Mycophenolate mofetil inhibits macrophageinfiltration and kidney fibrosis in long-term ischemiareperfusioninjury. Eur J Pharmacol. 2012;688(1-3):56-61. doi: 10.1016/j.ejphar.2012.05.001.
Ishii Y, Sawada T, Shimizu A, Tojimbara T, NakajimaI, Fuchinoue S, et al. An experimental sclerosingencapsulating peritonitis model in mice. NephrolDial Transplant. 2001;16(6):1262-6. doi: 10.1093/ndt/16.6.1262.
Fieren MW, Betjes MG, Korte MR, Boer WH.Posttransplant encapsulating peritoneal sclerosis: aworrying new trend? Perit Dial Int. 2007;27(6):619-24.
Korte MR, Habib SM, Lingsma H, Weimar W,Betjes MG. Posttransplantation encapsulatingperitoneal sclerosis contributes significantly tomortality after kidney transplantation. Am JTransplant. 2011;11(3):599-605. doi: 10.1111/j.1600-6143.2010.03434.x.
Waller JR, Brook NR, Bicknell GR, Nicholson ML.Differential effects of modern immunosuppressiveagents on the development of intimal hyperplasia.Transpl Int. 2004;17(1):9-14. doi: 10.1007/s00147-003-0653-8.
Gregory CR, Pratt RE, Huie P, Shorthouse R, DzauVJ, Billingham ME, et al. Effects of treatment withcyclosporine, FK 506, rapamycin, mycophenolic acid, ordeoxyspergualin on vascular muscle proliferation in vitroand in vivo. Transplant Proc. 1993;25(1 Pt 1):770-1.
Roos N, Poulalhon N, Farge D, Madelaine I, MauvielA, Verrecchia F. In vitro evidence for a direct antifibroticrole of the immunosuppressive drug mycophenolatemofetil. J Pharmacol Exp Ther. 2007;321(2):583-9. doi:10.1124/jpet.106.117051.
Badid C, Vincent M, McGregor B, Melin M, Hadj-AissaA, Veysseyre C, et al. Mycophenolate mofetil reducesmyofibroblast infiltration and collagen III deposition inrat remnant kidney. Kidney Int. 2000;58(1):51-61. doi:10.1046/j.1523-1755.2000.00140.x.
Manojlovic Z, Blackmon J, Stefanovic B. Tacrolimus(FK506) prevents early stages of ethanol induced hepaticfibrosis by targeting LARP6 dependent mechanism ofcollagen synthesis. PLoS One. 2013;8(6):e65897. doi:10.1371/journal.pone.006589.
Waller JR, Murphy GJ, Bicknell GR, Toomey D,Nicholson ML. Effects of the combination of rapamycinwith tacrolimus or cyclosporin on experimental intimalhyperplasia. Br J Surg. 2002;89(11):1390-5. doi:10.1046/j.1365-2168.2002.02271.x.
Luo L, Sun Z, Wu W, Luo G. Mycophenolatemofetil and FK506 have different effects on kidneyallograft fibrosis in rats that underwent chronicallograft nephropathy. BMC Nephrol. 2012;13:53. doi:10.1186/1471-2369-13-53.
Doller A, Akool el-S, Müller R, Gutwein P, KurowskiC, Pfeilschifter J, et al. Molecular mechanisms ofcyclosporin A inhibition of the cytokine-induced matrixmetalloproteinase-9 in glomerular mesangial cells. JAm Soc Nephrol. 2007;18(2):581-92. doi: 10.1681/ASN.2006060568.
Gagliano N, Moscheni C, Dellavia C, Stabellini G,Ferrario VF, Gioia M. Immunosuppression and gingivalovergrowth: gene and protein expression profiles ofcollagen turnover in FK506-treated human gingivalfibroblasts. J Clin Periodontol. 2005;32(2):167-73. doi:10.1111/j.1600-051X.2005.00654.x.