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CLINICAL AND TRANSLATIONAL RESEARCH

Impact of Conversion to an Once Daily TacrolimusBased Regimen in Kidney Transplant Recipients With Gastrointestinal Complications
Massimiliano Veroux,1,4 Giuseppe Grosso,2 Burcin Ekser,1,3 Daniela Corona,1 Alessia Giaquinta,1 and Pierfrancesco Veroux1
Background. Gastrointestinal (GI) complications may affect up to 64% of kidney transplant recipients, with a higher incidence of symptoms in patients receiving tacrolimus-based immunosuppression. Tacrolimus extended release oncedaily (OD) formulation offers the benefit of OD administration over standard tacrolimus, with a similar rate of GI complications when compared with the standard tacrolimus. We hypothesized that patients with tacrolimus-based immunosuppressive regimen with posttransplant gastrointestinal symptoms may benefit from a conversion to a tacrolimus OD regimen. Methods. In this pilot study, 27 kidney transplant recipients with tacrolimus-related GI complications were converted to a tacrolimus OD regimen (group 1). This group was compared with a historical cohort of 30 patients on standard tacrolimus therapy with GI symptoms (group 2). Patients were followed up for 1 year after initial enrollment. Results. Patients in group 1 reported a significant improvement in GI symptoms, as expressed by the change in the Gastrointestinal Symptom Rating Scale scores (1.70.3 vs. 1.20.2, P0.001) and GI-specific health-related quality of life scores (8726.3 vs. 9724.6, P0.05). After comparing changes in Gastrointestinal Symptom Rating Scale total scores and subscale scores at 12 months, patients in Group 1 scored better than patients in Group 2 in total scores (0.5 vs. 0.12, P0.0001), abdominal pain (P0.001), diarrhea (P0.001), and reflux (P0.013). Conclusions. Preliminary results from this study demonstrate that kidney transplant recipients experiencing tacrolimusinduced GI symptoms may benefit from a conversion to a tacrolimus OD regimen. Keywords: Kidney transplantation, Tacrolimus, Tacrolimus once-daily, Gastrointestinal complications, Diarrhea, Mycophenolate sodium. (Transplantation 2012;XX: 000000)

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idney transplantation is generally accepted as the optimal renal replacement therapy for most patients with endstage renal disease. Although advances in surgical techniques and immunosuppressive therapy have increased 1-year graft survival up to 90% (1), medical complications after trans-

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AQ: 3 The authors declare no funding or conflicts of interest.

Department of Surgery, Vascular Surgery and Organ Transplant Unit, Transplantation and Advanced Technologies, University Hospital of Catania, Catania, Italy. 2 Department G.F. Ingrassia, Section of Hygiene and Public Health, University Hospital of Catania, Catania, Italy. 3 Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA. 4 Address correspondence to: Massimiliano Veroux, M.D., Ph.D., Department of Surgery, Vascular Surgery and Organ Transplant Unit, Transplantation and Advanced Technologies, University Hospital of Catania, via Santa Sofia, 83 95128 Catania, Italy. E-mail: veroux@unict.it M.V. participated in research design and wrote the manuscript; G.G. participated in data analysis; B.E., D.C., and A.G. participated in the performance of the research; and P.V. participated in research design. Received 26 September 2011. Revision requested 13 October 2011. Accepted 28 December, 2011. Copyright 2011 by Lippincott Williams & Wilkins ISSN 0041-1337/11/XX0X-1 DOI: 10.1097/TP.0b013e318248ca90

plantation are common and may be associated with adverse posttransplant outcome, including graft loss (2). Gastrointestinal (GI) complications are a frequent cause of morbidity after transplantation and may affect up to 64% of kidney transplant recipients (3, 4), and may be associated to a doubled risk of graft loss and patient death (5). Immunosuppressive therapy is known to make transplant recipients susceptible to GI symptoms, with a higher incidence in patients receiving tacrolimus and mycophenolate mofetil (MMF) (5). Tacrolimus extended release once-daily (OD) formulation (6) offers the benefit of OD administration over standard tacrolimus, with an overall efficacy and tolerability profile similar to that of standard tacrolimus in stable and de novo kidney transplant recipients. Most of the studies investigating the rate of posttransplant complications have reported a similar rate of GI complications in patients treated with standard tacrolimus and with tacrolimus OD (7). We hypothesized that patients with tacrolimus/mycophenolate sodium (MPS) immunosuppressive regimen with posttransplant GI symptoms may benefit from a conversion to a tacrolimus OD regimen. For this purpose, a range of patientreported outcome instruments were used to monitor changes in GI symptom burden and health-related quality of life.
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RESULTS
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All 57 patients enrolled in both groups completed the study protocol. Patients characteristics were similar between the two groups and are summarized in Table 1. The most frequent GI symptoms reported before enrollment were diarrhea (75%), flatulence (65%), abdominal pain (70%), with dyspepsia, nausea, and constipation occurring in 43.5%, 40%, and 40%, respectively. Mean severity scores for flatulence and diarrhea improved to a significantly greater extent

in group 1 between visit 1 and visit 3. Mean Gastrointestinal Symptom Rating Scale (GSRS) score at visit 1 was 1.70.3 and at visit 3 was 1.20.2 (P0.001). As a result of such an improvement in GSRS total score, the improvement in mean scores was significant for abdominal pain (P0.001), reflux (P0.0041), indigestion (P0.001), and diarrhea (P0.001; Fig. 1). Analysis of single subscales found differences between visit 1 and visit 3 in abdominal pain (P0.001), heartburn (P0.046), acid regurgitation (P0.046), nausea and vomit-

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TABLE 1. Characteristics of study patients (n57) Group 1: tacrolimus once daily (n27) Gender (male) Recipient age (yr) Time on hemodialysis before transplantation (mo) Donor age (yr) Body mass index (kg/m2) Cause of end-stage renal disease Glomerulonephritis Polycystic kidney disease Hypertension Unknown Trough level tacrolimus at visit 1 (ng/mL) Trough level tacrolimus at visit 2 (ng/mL) Trough level tacrolimus at visit 3 (ng/mL) Dose of tacrolimus at visit 1 (mg/d) Dose of tacrolimus at visit 2 (mg/d) Dose of tacrolimus at visit 3 (mg/d) Dose of MPS at visit 1 (mg/d) Dose of MPS at visit 2 (mg/d) Dose of MPS at visit 3 (g/d) Mean serum creatinine at visit 1 (mg/dL) Mean serum creatinine at visit 2 (mg/dL) Mean serum creatinine at visit 3 (mg/dL)
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Group 2: standard tacrolimus (n30) 18 53.614.8 307.4 5910.1 244 19 4 1 6 6.21.3a 5.61.3a 5.60.7a 5.31.8a 5.21.1a 4.81.7a 1328178 1101248 884224 1.420.4 1.380.6 1.370.8

P 0.765 0.685 0.728 0.821 0.679 0.89 0.885 0.892 0.901 0.899 0.824 0.812 0.855 0.765 0.685 0.785 0.885 0.774 0.011 0.732 0.732 0.625

16 51.411.5 2911.4 5711.7 253 18 5 1 3 6.41.2a 5.71.5b 5.51.4b 5.52.6a 5.81.3b 5.51.4b 1315175 1224180 1140190 1.340.8 1.310.8 1.280.6

Standard tacrolimus. Tacrolimus once daily. MPS, mycophenolate sodium; Visit 1, enrollment; Visit 2, 6 mo after enrollment; Visit 3, 1 yr after enrollment.

FIGURE 1. Change in mean Gastrointestinal Symptom Rating Scale scores from visit 1 to visit 3 in group 1 patients. Higher scores represent greater symptom burden.

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FIGURE 2. Change in mean Gastrointestinal Symptom Rating Subscale scores from visit 1 to visit 3 in group 1 patients. Higher scores represent greater symptom burden.

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ing/reflux (P0.004), abdominal distension and flatulence (P0.001), eructation (P0.015), and increased passage of stools/diarrhea (P0.001; Fig. 2). At visit 1, the mean Gastrointestinal Quality of Life Index (GIQLI) score was 8726.3 and 86.220.1 in group 1 and in group 2, respectively (P0.798). As observed with GSRS, at visit 3, we observed a significant improvement in total GIQLI total score in group 1 (9724.6, P0.05) but not in group 2 (88.512.6, P0.632), and the mean overall and subscale scores significantly improved (P0.05) after conversion to tacrolimus OD. GSRS total scores in group 2 improved from visit 1 to visit 3 (1.710.19 vs. 1.520.3), but these did not reach statistical significance (P0.058). After comparing changes in GSRS total scores and subscale scores from visit 1 to visit 3 between group 1 and group 2, significant differences were found in total scores (0.5 vs. 0.12, P0.0001), abdominal pain (P0.001), reflux (P0.013) and diarrhea (P0.001) (Fig. 3). Total dose of tacrolimus OD was slightly higher than standard tacrolimus after conversion, but whole blood concentration was not significantly different after conversion. Whole blood concentration was lower in group 2, but not statistically significant while the MPS dose was significantly lower at visit 3, suggesting a significant reduction in immunosuppression to contrast the GI complications. There were no graft losses or death in both groups. There were no acute rejection episodes among patients in group 1, whereas two patients in group 2 experienced a biopsy-proven acute rejection episode (one T-cell mediated rejection Banff 07 type IA and 1 type IIA) during the study period (P0.727). One patient in group 1 developed a new-onset diabetes mellitus, whereas three other patients required a dose adjustment due to neutropenia. One patient discontinued the drug 3 months after conversion and returned to standard tacrolimus regimen because of worsening GI symptoms, severe anemia and neutropenia.

FIGURE 3. Change in Gastrointestinal Symptom Rating Scale (GSRS) total score and subscale scores from visit 1 to visit 3 among converted patients (group 1) and standard tacrolimus therapy patients (group 2). Values shown are mean LSM change.

In group 1, 17 patients (62.9%) reported a significant improvement of GI symptoms, 6 patients (22.2%) reported low/moderate improvements, whereas 4 (14.8%) patients reported no improvements in GI symptoms after the conver-

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sion to tacrolimus OD. In group 2, 6 (20%) patients reported a significant improvement of GI symptoms, 8 patients (26.6%) reported low/moderate improvements, whereas 16 (53.3%) patients reported no improvements in GI symptoms. Graft function was stable during the study period. Mean serum creatinine at visit 1 was 1.34 mg/dL, whereas at visit 3, it was 1.28 mg/dL (P0.835) in group 1, and 1.42 mg/dL and 1.37 mg/dL (P0.842) in group 2.

DISCUSSION
This is the first pilot study demonstrating that tacrolimusinduced GI symptoms in kidney transplant recipients may be reduced or improved after conversion to tacrolimus OD regimen. Conversion to tacrolimus OD was associated with significant improvements in GI symptom burden and GIspecific Health-related quality of life (HRQoL) as compared with standard tacrolimus, as assessed by validated patientreported outcome instruments. GI symptoms are a common cause of morbidity after kidney transplantation, and their incidence varies according to the symptom reported. In a recent study, Bunnapradist et al. (5) evaluated the incidence of posttransplant diarrhea in a large cohort of kidney transplant recipients. At 3-year posttransplantation, the incidence of diarrhea was 22% and posttransplantation diarrhea doubled the risk of graft loss, patient death, and death-censored graft survival. Immunosuppression has a critical role in determining GI symptoms, and recipients with the combination of tacrolimus and MMF have a greater incidence of GI complications (5). Many strategies have been advocated to reduce the incidence of GI symptoms. Dose reduction or discontinuation may be beneficial but may result in inadequate immunosuppression and lead to worse graft and patient survival rates (8, 9). Although recent data suggest that changes from MMF to enteric-coated MPS may be beneficial and may improve GIsymptom burden and increase GI-specific HRQoL in patients experiencing GI symptoms (10), there are no significant differences in improvement in the long term between patients treated with MMF and those treated with enteric-coated MPS (11). We assessed the safety and efficacy of a conversion protocol from standard tacrolimus to tacrolimus OD in a population of kidney transplant recipients with GI symptoms. GI symptoms were assessed with two self-administered patient questionnaires that had been previously validated in kidney transplant recipients and that performed better than generic patient-reported outcome instruments (11, 12). Tacrolimus extended-release formulation has been developed as a OD tacrolimus dosing alternative that enables the same patient care strategies and therapeutic monitoring techniques as used with standard tacrolimus. Most recent trials have demonstrated that tacrolimus OD has a similar rate of acute rejection and a similar rate of patient and graft survival compared with standard tacrolimus (1316). The tolerability of tacrolimus OD and standard tacrolimus compared with cyclosporine has been assessed in a large, randomized, nonblind trial (13). The incidence of diarrhea in de novo transplant recipients was not different between tacrolimus OD and standard tacrolimus (45.3% vs. 44.3%, respectively), whereas the incidence of loose stools was significantly higher among the patients on standard tacrolimus

(5.1% vs. 7.1%, respectively, P0.05). Similar findings have been recently reported in a multicenter, randomized noninferiority study comparing the efficacy and safety of standard tacrolimus and tacrolimus OD in 667 de novo kidney transplant recipients. In their study, Kra mer et al. (14) found no statistical difference in rate of GI complications between the two immunosuppressive protocols. However, similar data in patients converted to tacrolimus OD from standard tacrolimus therapy were not fully reported in literature. The preliminary findings of our study are surprising in that the conversion to tacrolimus OD resulted in a significant improvement of GI symptom burden and this improvement was maintained at the 12-month postconversion followup when compared with patients on standard tacrolimus therapy. There is not a clear explanation for these results: most of our patients reported the onset of the GI symptoms immediately after the assumption of tacrolimus, when the whole blood concentration is at its highest level. Alloway et al. (17), in their pharmacokinetic study to evaluate tacrolimus exposure in stable kidney transplant recipients converted from tacrolimus twice a day to OD tacrolimus, showed that the assumption of tacrolimus OD was associated with a reduced Cmax, as expressed by the reduced whole blood concentration 2 hr after assumption. We may postulate that, in susceptible patients, this lower concentration of tacrolimus immediately after its assumption may be beneficial, reducing acute exposure to the drug, and may, finally, play a significant role in the improvement of GI symptoms. A similar effect was noted in our tacrolimus-treated patients who were converted to tacrolimus OD regimen due to neurotoxicity (tremors, headache): most of these transplant recipients reported an improvement of their symptoms after conversion (data not shown). There are some limits to the study. First, we recognize that a placebo-effect may have played a role in the improved patient-reported outcomes after conversion: to reduce this effect, patients completed the scores 1 year after enrollment. Second, the role of MPS may be a potential disturbing confounder: however, in patients converted to tacrolimus OD, the dose of MPS has not significantly changed 1 year after conversion; on contrast, in patients remaining in standard tacrolimus therapy, the dose of MPS was significantly lower at 1-year follow up, without clear improvements in GI symptoms. Finally, the study population was small. However, this is a homogeneous group of patients with the same immunosuppressive regimen and similar baseline characteristics and the data may be applicable to larger study populations. In conclusion, preliminary results from this study demonstrate that kidney transplant recipients experiencing tacrolimus-induced GI symptoms may benefit from a conversion to tacrolimus OD regimen. The conversion was associated with improved GI symptom burden and HRQoL as compared with standard tacrolimus-treated patients and this effect was maintained at 1 year after conversion. At equivalent doses, tacrolimus OD regimen was associated with equivalent graft function with no increased risk of acute rejection. Tacrolimus OD regimen seems to offer a safe therapeutic alternative when seeking to reduce tacrolimusrelated GI symptoms.

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MATERIALS AND METHODS Study Design and Procedures

This study was performed on patients who signed an informed consent form, using an immunosuppressive protocol approved by our ethical committee. In this single-center, prospective study, 27 adults, who had undergone a primary kidney transplantation from a deceased donor between 2007 and 2010, were enrolled (group 1). These patients were compared with a historical cohort of 30 patients on standard tacrolimus therapy, who had been previously enrolled to study the relationship between tacrolimus trough levels and GI symptoms (unpublished data). The inclusion criteria for entering into the study protocol were the following: (1) kidney transplantation performed at least 3 months before inclusion, (2) stable renal function, (3) no evidence of rejection in the previous 3 months, (4) tacrolimus-based immunosuppression, (5) MPS administered as adjunctive therapy, (6) corticosteroid therapy (prednisone 5 mg/day), and (7) presence of GI symptoms, not attributable to infectious disease, that had previously necessitated a reduction in MPS dose and which were now present but tolerated or with GI symptoms that would require a dose reduction of MPS. Tacrolimus blood concentrations were measured with a total heterogeneous electrochemical luminescence immunoassay, and patient visits occurred 7, 14, and 30 days after enrollment and every month thereafter. When dose adjustments were necessary, a patient visit was given 14 days after adjustment. Patients were followed-up for 12 months after enrollment. Clinical status (body weight, blood pressure) and laboratory parameters (serum creatinine, glycemia, hemoglobin, and alanine aminotransferase) were monitored at each clinical visit.

2. 3.

4. 5. 6.

7. 8.

9.

10.

11.

Patient Reported Outcome and Evaluation

After screening (visit 1), patients in group 1 were converted on a 1 mg:1 mg basis to tacrolimus OD, whereas group 2 patients were on standard tacrolimus therapy. Two self-administered patient questionnaires were used in the study. The GSRS assesses GI symptoms based on responses to 15 questions grouped into five subscales (reflux, diarrhea, constipation, abdominal pain, and indigestion). Scores range from 1 to 7, where higher scores represent greater symptom burden (18 20). HRQoL was assessed using the GIQLI in which a total score of up to 144 can be calculated from individual scores in response to 36 questions, with higher scores indicating better GI-specific HRQoL (21). The presence of GI symptoms (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, and nausea) was recorded at the time of enrollment (visit 1) and after 6 months (visit 2), and 1 year (visit 3) in both groups. Patients completed the GSRS and GIQLI scores at visit 1 and visit 3. Patients completed questionnaires before any clinical evaluation or procedure. 12. 13.

14.

15.

16.

Endpoints
The primary efficacy end-points were (1) the proportion of patients at visit 3 who showed an improvement of GI symptoms among patients in Group 1, and (2) significant improvement of GI symptoms in group 1 compared with group 2. Secondary end-points were the incidence of biopsyproven acute rejection and renal function after enrollment. 17.

18. 19. 20. 21.

Statistical Analyses
Significant differences in GSRS and GIQLI between visit 1 and visit 3 in group 1 were assessed by Wilcoxon two-sample tests; changes from visit 1 to visit 3 in both groups were compared with the Mann-Whitney U test.

REFERENCES
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Adams PL. Long-term patient survival: Strategies to improve overall health. Am J Kidney Dis 2006(suppl 2): 47: S65. Miller J, Mendez R, Pirsch JD, et al. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group. Transplantation 2000; 69: 875. Squifflet JP, Backman L, Claesson K, et al. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients. Transplantation 2001; 72: 63. Bunnapradist S, Neri L, Wong W, et al. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. Am J Kidney Dis 2008; 51: 478. European Medicines Agency. Advagraf: Summary of product regimen to a once-daily modified release tacrolimus-based characteristics [online]. Available at: http://www. emea.europa.eu. Accessed June 29, 2007. Cross SA, Perry CM. Tacrolimus once-daily formulation in the prophylaxis of transplant rejection in renal or liver allograft recipients. Drugs 2007; 67: 1931. Bunnapradist S, Lentine KL, Burroughs TE, et al. Mycophenolate mofetil dose reduction and discontinuation after gastrointestinal complications are associated with renal transplant graft failure. Transplantation 2006; 82: 102. Su VC, Greanya ED, Ensom MH. Impact of mycophenolate mofetil dose reduction on allograft outcomes in kidney transplant recipients on tacrolimus-based regimens: A systematic review. Ann Pharmacother In press. AQ: 1 Chan L, Mulgaonkar S, Walker R, et al. Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation 2006; 81: 1290. Shehata M, Bhandari S, Venkat-Raman G, et al. Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation. Transpl Int 2009; 22: 821. Kleinman L, Kilburg A, Machnicki G, et al. Using GI-specific patient outcomes measures in renal transplant patients: Validation of the GSRS and GIQLI. Qual Life Res 2006; 15: 1223. Silva HT Jr, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007; 7: 595. Kra mer BK, Charpentier B, Ba ckman L, et al. Tacrolimus Prolonged Release Renal Study Group. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: A randomized phase III study. Am J Transplant 2010; 10: 2632. van Hooff JP, Alloway RR, Trunec ka P, et al. Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant 2011; 25: E1. Guirado L, Cantarell C, Franco A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant 2011; 11: 1965. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc 2005; 37: 867. Dimena s E, Glise H, Hallerback B, et al. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993; 28: 681. Dimena s E, Glise H, Hallerback B, et al. Well being and gastrointestinal symptoms among patients referred to endoscopy owing to suspected duodenal ulcer. Scand J Gastroenterol 1995; 30: 1046. Revicki DA, Wood M, Wiklund I, et al. Reliability and validity of the Gastrointestinal symptom rating scale in patients with gastroesophageal reflux disease. Qual Life Res 1998; 7: 75. Eypasch E, Williams JI, Wood-Dauphinee S, et al. Gastrointestinal quality of life index: Development, validation and application of a new instrument. Br J Surg 1995; 82: 216.

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AUTHOR QUERIES
AUTHOR PLEASE ANSWER ALL QUERIES
AQ1 Please update Ref. 9. AQ2 Please spell out the abbreviation LSM in the legend of Fig. 3. AQ3 Please confirm that there is no funding or conflicts of interest to disclose. 1