Accepted Article
Received Date : 26-Mar-2014 Revised Date : 03-Aug-2014 Accepted Date : 13-Aug-2014 Article type
: Original Article
Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients.
Andrade, LGM; Rodriges,MAM; Romeiro, FG; Garcia, PD; Contti, MM; Carvalho, MFC Luis Gustavo Modelli de Andrade Department of Internal Medicine - UNESP, Univ Estadual Paulista Participated in the performance of the research; Analysis and interpretation of data Maria Aparecida Marchesan Rodrigues Department of Pathology - UNESP, Univ Estadual Paulista
Participated in research design Fernando Gomes Romeiro Department of Internal Medicine - UNESP, Univ Estadual Paulista
Participated in research design Paula Dalsoglio Garcia Department of Internal Medicine - UNESP, Univ Estadual Paulista
Participated in research design
Mariana Moraes Contti Department of Internal Medicine - UNESP, Univ Estadual Paulista
Participated in research design Maria Fernanda Cordeiro de Carvalho Department of Internal Medicine - UNESP, Univ Estadual Paulista Conception and design; Final approval of the version to be published Running Head: Clinical of mycophenolic acid-related colitis
Corresponding author
Luís Gustavo Modelli de Andrade Department of Internal Medicine - UNESP, Univ Estadual Paulista
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ctr.12452 This article is protected by copyright. All rights reserved.
Accepted Article
Rubião Jr, s/n – Botucatu/SP ZIP Code: 18.618-970 Brazil Tel/Fax: 55 (14) 3811-6547 Email: [email protected]
Andrade, LGM; Rodriges,MAM; Romeiro, FG; Garcia, PD; Contti, MM; Carvalho, MFC
Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients. ABSTRACT
Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000-2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. CMV immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were nonspecific colitis (31.3%), IBD-like colitis (25%), normal/near normal (18.8%), graft-vs-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18. 75%). No graft loss occurred. Four patients died during the
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Accepted Article
study period. Late onset MPA was more frequent, and no correlation with MPA dose or formulation was found.
Key Words: Mycophenolic acid; Diarrhea, colitis; kidney transplant
Introduction Diarrhea is common in solid organ transplant recipients, and is generally ascribed to the adverse effects of immunosuppressive or non-immunosuppressive drugs, or infections (1). Mycophenolic acid (MPA) is an important immunosuppressive agent routinely used in the maintenance of immunosuppression for transplant recipients. MPA can lead to toxic injuries including ulcerative esophagitis, reactive gastropathy, and graft-versus-host disease (GVHD)-like features in intestinal biopsies throughout the entire gastrointestinal tract (2). However, the most common adverse effect of MPA in transplant patients is watery afebrile diarrhea with an incidence reaching 36% in kidney transplant recipients (3,4). The histologic changes seen in patients with MPA-associated drug toxicity have been reported to mimic GVHD, inflammatory bowel disease, ischemia or acute selflimited colitis (5,6) . However, constant histological features and diagnostic patterns of MPA-related colitis have not yet been established clearly, while the pathogenesis remains under investigation (2). Furthermore, reports on the clinical course of the disease in kidney transplant recipients are scarce. Therefore, the objective of this study is to report the clinical and pathological features, risk factors, and progression of MPA-related colitis after kidney transplantation.
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Materials and methods All kidney transplant patients who were receiving MPA (either mycophenolate mofetil or mycophenolate sodium - n=580) and had colonic biopsies performed for persistent chronic diarrhea between 2000 and 2012 at the Kidney Transplantation Center of Botucatu Medical School Hospital, São Paulo State University- UNESP were included in the study. Diarrhea was defined as an increase in the frequency of defecation to three or more times per day.
MPA-related diarrhea was diagnosed based on a stepwise flowchart
similar to that used in the DIDACT (1) study that consisted of: reducing immunosuppressive and nonimmunosuppressive diarrhea-inducing drugs; performing microbiological stool examination including cultures for parasites, Cryptosporidia, Isospora belli, Clostridium difficile, and rotavirus; excluding cytomegalovirus (CMV) infection through a CMV pp65 Antigenemia Immunofluorescence Assay; excluding bacterial overgrowth; and, performing a colonoscopy with biopsies for histological examination when diarrhea had still not resolved after 1-2 weeks. Before colonoscopy, 1 year of MPA use (mean time of onset 49.8meses). Liapis et al, however, suggests that MPA-related colitis may manifest within the first 2 years after MPA introduction, or may appear
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Accepted Article
later (2). Similarly, Maes et al reported that in >50% of patients, MPA-related diarrhea started 2 years or more post-transplantation (1). The demographic/clinical characteristics of the 16 patients with MPA-related colitis included in this study did not differ from those of MPA users without colitis (n=546), indicating that there is no predisposition towards the disease. The histologic changes observed in this study were those described by Selbst et al (5) in a series of solid organ transplant patients who underwent colonic biopsy for gastrointestinal symptoms. However, rather than the normal/near normal pattern reported by those authors, the most frequent pattern observed in our series was nonspecific colitis followed by IBD-like colitis. It is worth of note that due to the histologic similarities of MPA-related colitis with other conditions (5,7,8,11,12) that can pose diagnostic and management difficulties, pathologists should be aware of the histologic spectrum of MPA-induced changes in order to avoid diagnostic errors and unnecessary changes in immunosuppressive therapy (11,12). In this study, MPA-related colitis clinically manifested as severe diarrhea requiring hospitalization due to dehydration in 37.5% of the cases. Substituting another agent for MPA, or discontinuing MPA among our patients did not result in graft loss. On the other hand, Al-Albsi et al (12) observed graft loss in 3 of 5 of their patients. Thus, despite manifesting in a severe form, such as dehydration, in some of our cases, MPA-related colitis resolution was achieved by reducing or discontinuing MPA. The rate of death due to MPA-related colitis remains unreported by others. The fact that part of the patients included in this study were treated with mycophenolate mofetil (MMF), while the others received mycophenolate sodium This article is protected by copyright. All rights reserved.
Accepted Article
(MPS) did not seem to influence our results as similar doses were administered to all patients with colitis. In addition, no clinical, or even histopathological, difference in diarrhea episodes were observed between patients using MFS and those on MMF. Studies have shown that, regardless of its drug of origin (MMF or MPS), the rate and extent of MPA absorption is very similar for both MPS and MMF (17). One of the limitations of this study is that 62% of the participants were taking tacrolimus combined with MPA when colitis occurred. Tacrolimus is known to increase in MPA drug concentrations, and also to have a greater in-vitro immune-suppression effect. This is thought to be due to the fact that Tacrolimus does not inhibit the enterohepatic circulation of MPS in comparison to CSA, which inhibits the entero-hepatic circulation and subsequently limits the bioavailability of MPA (18). Thus, in general, Tacrolimus potentiates both gastro-intestinal and hematological side effects of MPA. Other limitations include this observational study’s retrospective design and small sample size. As a result, the study lacks information on: 1) the different clinical (in terms of severity, number of diarrhea cases) and pathological features , and risk factors for MMF versus MPS because of the small sample size of cases of diarrhea and colonoscopy-proven colitis; and 2) the number of patients with diarrhea who had diarrhea without colitis. Furthermore, the effects of confounding factors, such as the contribution of Tacrolimus versus CSA use to our findings, cannot be excluded.
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Accepted Article
Conclusion: MPA-related colitis should be considered in the differential diagnosis of patients taking this drug. In this study, MPA dose reduction or discontinuation resulted in good clinical outcome with diarrhea resolution and no graft loss. MPA-related colitis late onset being more frequent. No correlation with MPA dose or presentation (sodium or mofetil) was found.
The authors of this manuscript have no conflicts of interest to disclose
References 1.
Maes B, Hadaya K, de Moor B et al. Severe diarrhea in renal transplant patients: Results of the DIDACT study. Am J Transplant 2006: 6: 1466.
2.
Liapis G, Boletis J, Skalioti C et al. Histological spectrum of mycophenolate mofetil-related colitis: association with apoptosis. Histopathology 2013: 63: 649.
3.
Helderman JH, Goral Simin. Gastrointestinal Complications of Transplant Immunosuppression. J Am Soc Nephrol 2002: 13: 277.
4.
Davies NM, Grinyó J, Heading R, Maes B, Meier-Kriesche HU, Oellerich M. Gastrointestinal side effects of mycophenolic acid in renal transplant patients: a reappraisal. Nephrol Dial Transplant 2007: 22: 2440.
5.
Selbst MK, Ahrens WA, Robert ME, Friedman A, Proctor DD, Jain D. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Mod Pathol 2009: 22: 737.
6.
Lee S, de Boer WB, Subramaniam K, Kumarasinghe MP. Pointers and pitfalls of mycophenolate-associated colitis. J Clin Pathol 2013: 66: 8.
7.
Coyne JD, Campbell F. Microscopic features associated with mycophenolate mofetil in gastric and colonic biopsies. Histopathology 2012: 61, 993.
8.
Papadimitriou JC, Cangro CB, Lustberg A et al. Histologic Features of Mycophenolate Mofetil-Related Colitis: A Graft-Versus-Host Disease-Like Pattern. Int J Surg Pathol 2003: 11: 295.
09.
Olyaei AJ, de Mattos AM, Bennett WM. Pharmacology of immunosuppressive drugs. Drugs Today (Barc) 1998: 34: 463.
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Accepted Article
10.
Allison AC, Eugui EM. The design and development of an immunosuppressive drug, mycophenolate mofetil. Springer Semin Immunopathol 1993: 14: 353.
11.
Parfitt JR, Jayakumar S, Driman DK. Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versushost disease-like changes. Am J Surg Pathol 2008: 32: 1367.
12.
Al-Absi AI1, Cooke CR, Wall BM, Sylvestre P, Ismail MK, Mya M. Patterns of injury in mycophenolate mofetil-related colitis. Transplant Proc 2010: 42: 3591.
13.
Gorospe EC. Chronic diarrhoea from mycophenolate mofetil-induced colitis. BMJ Case Rep 2012: 2012.
14.
Keown P, Häyry P, Mathew T et al. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996: 61: 1029.
15.
Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection European Mycophenolate Mofetil Cooperative Study Group. Lancet 1995: 345: 1321.
16.
Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995: 60: 225.
17.
Arns W, Breuer S, Choudhury S et al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin. Transplant 2005: 19: 199.
18.
Naito T, Shinno K, Maeda T et al. Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation. Biol Pharm Bull 2006: 29: 275.
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Table 01. Clinical characteristics of 16 patients with mycophenolic acid-related colitis (N=16) Age (years) Male White Underlying disease
Living donor PRA (%) Mismatches (n) Rejection Time of MPA exposure (months) Histologic finding IBD like Nonspecific GVHD-like Ischemia-like
34.63 ± 12.874 50.0% 68.8% 6.3% 12.5% 50.0% 18.8% 12.5% 56.3% 25.63 ± 34.24 4.0 ± 1.51 31.3% 44.31 ± 33.48 25.0% 31.3% 12.5% 12.5%
Normal Calcineurin Inhibitors use MPA use Predinisone use Creatinine (mg/dl)
18.8% 87.5% 100% 93.8% 1.71 ± 0.59
Diabetes mellitus Hypertension Glomerulopnephritis Unknown Others
PRA- Panel react antibodies; GVHD- graft-versus-host disease; IBD- inflammatory bowel disease; MPA- mycophenolic acid
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Table 02. MPA-related colitis clinical course in 16 patients I A Se D g x e
Ra ce
ES RD
Don or
(y r)
Ti me on M M F
Col itis Ty pe
Immunos uppressio n
MPA dose/d ay
Action taken
Graft loss
Deat h
(mg)
M al e Fe m
Wh ite
CGN
Living
31
IBD like
Tacro+MFS +PDN
1080 MFS
Switch to SRL
No
No
Wh ite
Dece ased
37
IBD like
Tacr+MFS+ P
720 MFS
Discontinua tion
No
No
Wh ite
Living
111
IBD like
MMF+PDN
1500 MMF
Switch to AZA
No
No
Wh ite
Oth er
Living
12
IBD like
Tacr+MFS+ PDN
720 MFS
Switching to AZA
No
No
3 4
M al e M al e Fe m
unk now n Oth er
Wh ite
CGN
Living
123
MMF+PDN
1500 MMF
Switch to SRL
No
No
6
4 9
Fe m
Wh ite
Hyp erte nsio n
Dece ased
10
non spe cific non spe cific
Tacro+MFS +PDN
1440 MFS
50%-dose reduction
No
Death - HS
7
2 4
Fe m
No nWh ite
CGN
Dece ased
46
non spe cific
SRL+MFS+P DN
1080 MFS
50%-dose reduction
No
No
8
3 1
M al e
Wh ite
CGN
Living
48
non spe cific
MFS+PDN
1440 MFS
Switch to SRL
No
No
9
3 6
M al e
Wh ite
CGN
Dece ased
50
non spe cific
Tacro+MFS +PDN
720 MFS
Discontinua tion
No
No
1
2 3
2
3 9
3
1 0
4
5 2
5
CGN- chronic glomerulonephritis; HS – hemorrhagic stroke; PDN- prednisone; AZAazathioprine; CSA- cyclosporine; SRL-sirolimus; TACRO- tacrolimus; MMFmycophenolate mofetil; MFS- mycophenolate sodium.
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Accepted Article
Table 02 Cont. MPA-related colitis clinical course in 16 patients I A S Ra D g ex ce e
ES RD
Don or
(y r)
Ti me on M M F
Col itis Ty pe
Immunos uppressio n
MPA dose/d ay
Action taken
Graft loss
Deat h
(mg)
1 0
3 4
Fe m
No nWh ite
unk now n
Dece ased
33
GV HD
Tacro+MFS +PDN
1440 MFS
Switch to SRL
No
1 1 1 2
5 5
Fe m M al e
CGN
62
GV HD non spe cific
Tacro+MFS +PDN Tacro+MM F+PDn
1440 MFS
Switch to SRL
No
2000 MMF
Discontinu ation
No
No
4 9
Fe m
Hyp erte nsio n Diab etes
Dece ased Livin g
1 3
Wh ite No nWh ite No nWh ite
Deat hsepsi s unrel ate to colitis No
Dece ased
17
non spe cific
Tacr+MFS+ PDN
1440 MFS
50%-dose reduction
No
1 4 1 5
2 8
Fe m
Wh ite
Diab etes
Livin g
47
Nor mal
CSA+MMF +PDN
2000 MMF
Switch to SRL
No
Deat habdo minal sepsi s No
1 8
M al e
Diab etes
Livin g
59
Nor mal
CSA+MMF +PDN
2000 MMF
Switch to SRL
No
No
1 6
2 8
M al e
No nWh ite Wh ite
unk now n
Livin g
19
Nor mal
Tacr+MFS+ PDN
1080
Switch to SRL
No
Deat hcardi ovasc ular caus e
4 4
4
MFS
CGN- chronic glomerulonephritis; HS – hemorrhagic stroke; PDN- prednisone; AZAazathioprine; CSA- cyclosporine; SRL-sirolimus; TACRO- tacrolimus; MMFmycophenolate mofetil; MFS- mycophenolate sodium.
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Accepted Article
Figure01. Patient flowchart. *DIDATC protocol: reducing immunosuppressive and nonimmunosuppressive diarrheainducing drugs; performing microbiological stool examination including cultures for parasites, Cryptosporidia, Isospora belli, Clostridium difficile, and rotavirus; excluding cytomegalovirus
(CMV)
infection
through
a
CMV
pp65
Antigenemia
Immunofluorescence Assay; excluding bacterial overgrowth; and, performing a colonoscopy with biopsies for histological examination when diarrhea had still not resolved
This article is protected by copyright. All rights reserved.
Received Date : 26-Mar-2014 Revised Date : 03-Aug-2014 Accepted Date : 13-Aug-2014 Article type
: Original Article
Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients.
Andrade, LGM; Rodriges,MAM; Romeiro, FG; Garcia, PD; Contti, MM; Carvalho, MFC Luis Gustavo Modelli de Andrade Department of Internal Medicine - UNESP, Univ Estadual Paulista Participated in the performance of the research; Analysis and interpretation of data Maria Aparecida Marchesan Rodrigues Department of Pathology - UNESP, Univ Estadual Paulista
Participated in research design Fernando Gomes Romeiro Department of Internal Medicine - UNESP, Univ Estadual Paulista
Participated in research design Paula Dalsoglio Garcia Department of Internal Medicine - UNESP, Univ Estadual Paulista
Participated in research design
Mariana Moraes Contti Department of Internal Medicine - UNESP, Univ Estadual Paulista
Participated in research design Maria Fernanda Cordeiro de Carvalho Department of Internal Medicine - UNESP, Univ Estadual Paulista Conception and design; Final approval of the version to be published Running Head: Clinical of mycophenolic acid-related colitis
Corresponding author
Luís Gustavo Modelli de Andrade Department of Internal Medicine - UNESP, Univ Estadual Paulista
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ctr.12452 This article is protected by copyright. All rights reserved.
Accepted Article
Rubião Jr, s/n – Botucatu/SP ZIP Code: 18.618-970 Brazil Tel/Fax: 55 (14) 3811-6547 Email: [email protected]
Andrade, LGM; Rodriges,MAM; Romeiro, FG; Garcia, PD; Contti, MM; Carvalho, MFC
Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients. ABSTRACT
Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000-2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. CMV immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were nonspecific colitis (31.3%), IBD-like colitis (25%), normal/near normal (18.8%), graft-vs-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18. 75%). No graft loss occurred. Four patients died during the
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Accepted Article
study period. Late onset MPA was more frequent, and no correlation with MPA dose or formulation was found.
Key Words: Mycophenolic acid; Diarrhea, colitis; kidney transplant
Introduction Diarrhea is common in solid organ transplant recipients, and is generally ascribed to the adverse effects of immunosuppressive or non-immunosuppressive drugs, or infections (1). Mycophenolic acid (MPA) is an important immunosuppressive agent routinely used in the maintenance of immunosuppression for transplant recipients. MPA can lead to toxic injuries including ulcerative esophagitis, reactive gastropathy, and graft-versus-host disease (GVHD)-like features in intestinal biopsies throughout the entire gastrointestinal tract (2). However, the most common adverse effect of MPA in transplant patients is watery afebrile diarrhea with an incidence reaching 36% in kidney transplant recipients (3,4). The histologic changes seen in patients with MPA-associated drug toxicity have been reported to mimic GVHD, inflammatory bowel disease, ischemia or acute selflimited colitis (5,6) . However, constant histological features and diagnostic patterns of MPA-related colitis have not yet been established clearly, while the pathogenesis remains under investigation (2). Furthermore, reports on the clinical course of the disease in kidney transplant recipients are scarce. Therefore, the objective of this study is to report the clinical and pathological features, risk factors, and progression of MPA-related colitis after kidney transplantation.
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Accepted Article
Materials and methods All kidney transplant patients who were receiving MPA (either mycophenolate mofetil or mycophenolate sodium - n=580) and had colonic biopsies performed for persistent chronic diarrhea between 2000 and 2012 at the Kidney Transplantation Center of Botucatu Medical School Hospital, São Paulo State University- UNESP were included in the study. Diarrhea was defined as an increase in the frequency of defecation to three or more times per day.
MPA-related diarrhea was diagnosed based on a stepwise flowchart
similar to that used in the DIDACT (1) study that consisted of: reducing immunosuppressive and nonimmunosuppressive diarrhea-inducing drugs; performing microbiological stool examination including cultures for parasites, Cryptosporidia, Isospora belli, Clostridium difficile, and rotavirus; excluding cytomegalovirus (CMV) infection through a CMV pp65 Antigenemia Immunofluorescence Assay; excluding bacterial overgrowth; and, performing a colonoscopy with biopsies for histological examination when diarrhea had still not resolved after 1-2 weeks. Before colonoscopy, 1 year of MPA use (mean time of onset 49.8meses). Liapis et al, however, suggests that MPA-related colitis may manifest within the first 2 years after MPA introduction, or may appear
This article is protected by copyright. All rights reserved.
Accepted Article
later (2). Similarly, Maes et al reported that in >50% of patients, MPA-related diarrhea started 2 years or more post-transplantation (1). The demographic/clinical characteristics of the 16 patients with MPA-related colitis included in this study did not differ from those of MPA users without colitis (n=546), indicating that there is no predisposition towards the disease. The histologic changes observed in this study were those described by Selbst et al (5) in a series of solid organ transplant patients who underwent colonic biopsy for gastrointestinal symptoms. However, rather than the normal/near normal pattern reported by those authors, the most frequent pattern observed in our series was nonspecific colitis followed by IBD-like colitis. It is worth of note that due to the histologic similarities of MPA-related colitis with other conditions (5,7,8,11,12) that can pose diagnostic and management difficulties, pathologists should be aware of the histologic spectrum of MPA-induced changes in order to avoid diagnostic errors and unnecessary changes in immunosuppressive therapy (11,12). In this study, MPA-related colitis clinically manifested as severe diarrhea requiring hospitalization due to dehydration in 37.5% of the cases. Substituting another agent for MPA, or discontinuing MPA among our patients did not result in graft loss. On the other hand, Al-Albsi et al (12) observed graft loss in 3 of 5 of their patients. Thus, despite manifesting in a severe form, such as dehydration, in some of our cases, MPA-related colitis resolution was achieved by reducing or discontinuing MPA. The rate of death due to MPA-related colitis remains unreported by others. The fact that part of the patients included in this study were treated with mycophenolate mofetil (MMF), while the others received mycophenolate sodium This article is protected by copyright. All rights reserved.
Accepted Article
(MPS) did not seem to influence our results as similar doses were administered to all patients with colitis. In addition, no clinical, or even histopathological, difference in diarrhea episodes were observed between patients using MFS and those on MMF. Studies have shown that, regardless of its drug of origin (MMF or MPS), the rate and extent of MPA absorption is very similar for both MPS and MMF (17). One of the limitations of this study is that 62% of the participants were taking tacrolimus combined with MPA when colitis occurred. Tacrolimus is known to increase in MPA drug concentrations, and also to have a greater in-vitro immune-suppression effect. This is thought to be due to the fact that Tacrolimus does not inhibit the enterohepatic circulation of MPS in comparison to CSA, which inhibits the entero-hepatic circulation and subsequently limits the bioavailability of MPA (18). Thus, in general, Tacrolimus potentiates both gastro-intestinal and hematological side effects of MPA. Other limitations include this observational study’s retrospective design and small sample size. As a result, the study lacks information on: 1) the different clinical (in terms of severity, number of diarrhea cases) and pathological features , and risk factors for MMF versus MPS because of the small sample size of cases of diarrhea and colonoscopy-proven colitis; and 2) the number of patients with diarrhea who had diarrhea without colitis. Furthermore, the effects of confounding factors, such as the contribution of Tacrolimus versus CSA use to our findings, cannot be excluded.
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Accepted Article
Conclusion: MPA-related colitis should be considered in the differential diagnosis of patients taking this drug. In this study, MPA dose reduction or discontinuation resulted in good clinical outcome with diarrhea resolution and no graft loss. MPA-related colitis late onset being more frequent. No correlation with MPA dose or presentation (sodium or mofetil) was found.
The authors of this manuscript have no conflicts of interest to disclose
References 1.
Maes B, Hadaya K, de Moor B et al. Severe diarrhea in renal transplant patients: Results of the DIDACT study. Am J Transplant 2006: 6: 1466.
2.
Liapis G, Boletis J, Skalioti C et al. Histological spectrum of mycophenolate mofetil-related colitis: association with apoptosis. Histopathology 2013: 63: 649.
3.
Helderman JH, Goral Simin. Gastrointestinal Complications of Transplant Immunosuppression. J Am Soc Nephrol 2002: 13: 277.
4.
Davies NM, Grinyó J, Heading R, Maes B, Meier-Kriesche HU, Oellerich M. Gastrointestinal side effects of mycophenolic acid in renal transplant patients: a reappraisal. Nephrol Dial Transplant 2007: 22: 2440.
5.
Selbst MK, Ahrens WA, Robert ME, Friedman A, Proctor DD, Jain D. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Mod Pathol 2009: 22: 737.
6.
Lee S, de Boer WB, Subramaniam K, Kumarasinghe MP. Pointers and pitfalls of mycophenolate-associated colitis. J Clin Pathol 2013: 66: 8.
7.
Coyne JD, Campbell F. Microscopic features associated with mycophenolate mofetil in gastric and colonic biopsies. Histopathology 2012: 61, 993.
8.
Papadimitriou JC, Cangro CB, Lustberg A et al. Histologic Features of Mycophenolate Mofetil-Related Colitis: A Graft-Versus-Host Disease-Like Pattern. Int J Surg Pathol 2003: 11: 295.
09.
Olyaei AJ, de Mattos AM, Bennett WM. Pharmacology of immunosuppressive drugs. Drugs Today (Barc) 1998: 34: 463.
This article is protected by copyright. All rights reserved.
Accepted Article
10.
Allison AC, Eugui EM. The design and development of an immunosuppressive drug, mycophenolate mofetil. Springer Semin Immunopathol 1993: 14: 353.
11.
Parfitt JR, Jayakumar S, Driman DK. Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versushost disease-like changes. Am J Surg Pathol 2008: 32: 1367.
12.
Al-Absi AI1, Cooke CR, Wall BM, Sylvestre P, Ismail MK, Mya M. Patterns of injury in mycophenolate mofetil-related colitis. Transplant Proc 2010: 42: 3591.
13.
Gorospe EC. Chronic diarrhoea from mycophenolate mofetil-induced colitis. BMJ Case Rep 2012: 2012.
14.
Keown P, Häyry P, Mathew T et al. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996: 61: 1029.
15.
Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection European Mycophenolate Mofetil Cooperative Study Group. Lancet 1995: 345: 1321.
16.
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Arns W, Breuer S, Choudhury S et al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin. Transplant 2005: 19: 199.
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Accepted Article
Table 01. Clinical characteristics of 16 patients with mycophenolic acid-related colitis (N=16) Age (years) Male White Underlying disease
Living donor PRA (%) Mismatches (n) Rejection Time of MPA exposure (months) Histologic finding IBD like Nonspecific GVHD-like Ischemia-like
34.63 ± 12.874 50.0% 68.8% 6.3% 12.5% 50.0% 18.8% 12.5% 56.3% 25.63 ± 34.24 4.0 ± 1.51 31.3% 44.31 ± 33.48 25.0% 31.3% 12.5% 12.5%
Normal Calcineurin Inhibitors use MPA use Predinisone use Creatinine (mg/dl)
18.8% 87.5% 100% 93.8% 1.71 ± 0.59
Diabetes mellitus Hypertension Glomerulopnephritis Unknown Others
PRA- Panel react antibodies; GVHD- graft-versus-host disease; IBD- inflammatory bowel disease; MPA- mycophenolic acid
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Accepted Article
Table 02. MPA-related colitis clinical course in 16 patients I A Se D g x e
Ra ce
ES RD
Don or
(y r)
Ti me on M M F
Col itis Ty pe
Immunos uppressio n
MPA dose/d ay
Action taken
Graft loss
Deat h
(mg)
M al e Fe m
Wh ite
CGN
Living
31
IBD like
Tacro+MFS +PDN
1080 MFS
Switch to SRL
No
No
Wh ite
Dece ased
37
IBD like
Tacr+MFS+ P
720 MFS
Discontinua tion
No
No
Wh ite
Living
111
IBD like
MMF+PDN
1500 MMF
Switch to AZA
No
No
Wh ite
Oth er
Living
12
IBD like
Tacr+MFS+ PDN
720 MFS
Switching to AZA
No
No
3 4
M al e M al e Fe m
unk now n Oth er
Wh ite
CGN
Living
123
MMF+PDN
1500 MMF
Switch to SRL
No
No
6
4 9
Fe m
Wh ite
Hyp erte nsio n
Dece ased
10
non spe cific non spe cific
Tacro+MFS +PDN
1440 MFS
50%-dose reduction
No
Death - HS
7
2 4
Fe m
No nWh ite
CGN
Dece ased
46
non spe cific
SRL+MFS+P DN
1080 MFS
50%-dose reduction
No
No
8
3 1
M al e
Wh ite
CGN
Living
48
non spe cific
MFS+PDN
1440 MFS
Switch to SRL
No
No
9
3 6
M al e
Wh ite
CGN
Dece ased
50
non spe cific
Tacro+MFS +PDN
720 MFS
Discontinua tion
No
No
1
2 3
2
3 9
3
1 0
4
5 2
5
CGN- chronic glomerulonephritis; HS – hemorrhagic stroke; PDN- prednisone; AZAazathioprine; CSA- cyclosporine; SRL-sirolimus; TACRO- tacrolimus; MMFmycophenolate mofetil; MFS- mycophenolate sodium.
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Accepted Article
Table 02 Cont. MPA-related colitis clinical course in 16 patients I A S Ra D g ex ce e
ES RD
Don or
(y r)
Ti me on M M F
Col itis Ty pe
Immunos uppressio n
MPA dose/d ay
Action taken
Graft loss
Deat h
(mg)
1 0
3 4
Fe m
No nWh ite
unk now n
Dece ased
33
GV HD
Tacro+MFS +PDN
1440 MFS
Switch to SRL
No
1 1 1 2
5 5
Fe m M al e
CGN
62
GV HD non spe cific
Tacro+MFS +PDN Tacro+MM F+PDn
1440 MFS
Switch to SRL
No
2000 MMF
Discontinu ation
No
No
4 9
Fe m
Hyp erte nsio n Diab etes
Dece ased Livin g
1 3
Wh ite No nWh ite No nWh ite
Deat hsepsi s unrel ate to colitis No
Dece ased
17
non spe cific
Tacr+MFS+ PDN
1440 MFS
50%-dose reduction
No
1 4 1 5
2 8
Fe m
Wh ite
Diab etes
Livin g
47
Nor mal
CSA+MMF +PDN
2000 MMF
Switch to SRL
No
Deat habdo minal sepsi s No
1 8
M al e
Diab etes
Livin g
59
Nor mal
CSA+MMF +PDN
2000 MMF
Switch to SRL
No
No
1 6
2 8
M al e
No nWh ite Wh ite
unk now n
Livin g
19
Nor mal
Tacr+MFS+ PDN
1080
Switch to SRL
No
Deat hcardi ovasc ular caus e
4 4
4
MFS
CGN- chronic glomerulonephritis; HS – hemorrhagic stroke; PDN- prednisone; AZAazathioprine; CSA- cyclosporine; SRL-sirolimus; TACRO- tacrolimus; MMFmycophenolate mofetil; MFS- mycophenolate sodium.
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Accepted Article
Figure01. Patient flowchart. *DIDATC protocol: reducing immunosuppressive and nonimmunosuppressive diarrheainducing drugs; performing microbiological stool examination including cultures for parasites, Cryptosporidia, Isospora belli, Clostridium difficile, and rotavirus; excluding cytomegalovirus
(CMV)
infection
through
a
CMV
pp65
Antigenemia
Immunofluorescence Assay; excluding bacterial overgrowth; and, performing a colonoscopy with biopsies for histological examination when diarrhea had still not resolved
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