Comparison of the Efficacy and Safety of Sirolimus, Everolimus or Mycophenolate in Renal Transplant Recipients Receiving Induction With Anti-thymocyte Globulin, Tacrolimus and Prednisone
Phase: PHASE4
Conditions: Kidney Transplant Infection
Sponsor: Hospital do Rim e Hipertensão

 
 
 
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Comparison of the Efficacy and Safety of Sirolimus, Everolimus or Mycophenolate in 
Renal Transplant Recipients Receiving Induction with Anti-thymocyte Globulin, 
Tacrolimus and Prednisone   
 
 
 
 
 
 
Date of document: 03/november/2020, amendment 7 
 
 
 
 
 
 
 
 
 
Responsible Researcher: Helio Tedesco Silva Junior 
 

 
 
 
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1. Introduction 
 
1.1 Cytomegalovirus infection 
Induction therapy with an anti-interleukin monoclonal antibody (anti-IL2Ra) 
followed by maintenance therapy with tacrolimus (TAC), mycophenolate (MPA) and 
prednisone is currently considered the standard immunosuppressive regimen by most 
transplant centers and regulatory agencies. (1). Use of this regimen is associated with a 
low incidence of acute rejection and superior renal function at one year (2). However, 
recent data suggest that the use of anti-IL2Ra in kidney transplant recipients using TAC 
and MPA does not produce a significant additional reduction in the incidence of acute 
rejection. With this triple maintenance therapy, the addition of anti-IL2Ra induction 
can achieve an absolute risk reduction for acute rejection of only 1-4% in standard risk 
patients without improving graft or patient survival (3). A recent meta-analysis 
including 71 studies showed that the use of anti-thymocyte globulin (r-ATG) is 
associated with a 30% reduction in the incidence of biopsy-confirmed acute rejection, 
but with a 75% increase in malignancy and a 32% increase in increased incidence of 
CMV disease compared to anti-IL2Ra (4). In patients at high immunological risk, 
induction of r-ATG reduces the relative risk of acute rejection by almost 50% compared 
with anti-IL2Ra (3). 
Cytomegalovirus (CMV) infection in solid organ transplant recipients is associated 
with “direct” and “indirect” effects that include graft rejection, predisposition to 
opportunistic fungal and bacterial infections, and higher incidence of malignancies, 
increasing morbidity and decreasing graft and patient survival. Risk factors associated 
with the development of CMV infection are the serological profile of recipients and 
donors, the type of immunosuppressive regimen, and the treatment of acute rejection 
(5). A recent review of 29 studies suggested that MPA-containing immunosuppression 
regimens are associated with an increased likelihood of developing CMV infection (6). 
Universal prophylaxis and preemptive therapies are strategies used after solid 
organ transplantation to control CMV infection. The major advantage of prophylaxis is 
the inhibition of virus replication, preventing the direct and indirect effects of CMV 
infection. On the other hand, the antiviral drugs used can cause adverse reactions, are 
expensive, and a significant proportion of patients end up developing CMV infection 
after stopping prophylaxis. Preemptive therapy allows treatment to be indicated only 

 
 
 
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for patients with virus replication. Both strategies have advantages and disadvantages 
in terms of effectiveness, safety and costs to the health system (5). 
Experimental and clinical data suggest that mTOR (mammalian target of 
rapamycin) inhibitors sirolimus (SRL) and everolimus (EVR) may limit CMV replication. 
A recent meta-analysis concluded that treatment with an mTOR inhibitor (imTOR), 
alone or in combination with calcineurin inhibitors, significantly reduces the incidence 
of CMV after organ transplantation, suggesting that with the use of an imTOR, 
prophylaxis for CMV infection could be expendable (7). 
In a recent study we compared the incidence of CMV infection/disease in kidney 
transplant recipients receiving EVR or MPA and no pharmacological prophylaxis for 
CMV infection. 288 patients were randomized to receive a single 3 mg/kg dose of r-
ATG, TAC, EVR and prednisone (r-ATG/EVR, n=85), basiliximab (BAS), TAC, EVR and 
prednisone (BAS/EVR , n=102) or BAS, TAC, MPA and prednisone (BAS/MPS, n=101). 
The incidence of CMV infection/disease was significantly lower in the everolimus-
treated patient groups (r-ATG/EVR 4.7% vs. BAS/EVR 10.8% vs. BAS/MPS 37.6%, 
p<0.001). There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 
15.8%, p=0.403), wound healing complications, delayed graft function and proteinuria. 
The estimated mean glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 
60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p=0.021). The reduced incidence of CMV infection 
observed in this study suggests that even preemptive treatment may be restricted to 
only those patients at highest risk for CMV infection, further reducing the costs of 
transplant center management (8). 
 
1.2 Objective 
 
This study was designed to assess the influence of using SRL or EVR (controlled for 
their residual blood concentrations) with TAC (reduced residual blood concentrations) 
compared to MPA (fixed doses) with TAC (standard residual blood concentrations) with 
regard to to efficacy and safety in de novo kidney transplant recipients. 
The primary outcome is the incidence of CMV infection/disease, a relevant medical 
need in the absence of pharmacological prophylaxis due to its morbidity and costs 
incurred by the public health system. This outcome represents an attempt to reduce 
the negative influence of this infection on the outcome of the transplant and on the 

 
 
 
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management of health resources, provided that the other key variables of efficacy and 
safety of these immunosuppression regimens are not inferior to those demonstrated 
by standard treatment. 
 
 
2. Research plan 
2.1 Study design: 
 
This prospective, randomized, single-center clinical study was designed to compare the 
safety and efficacy of three immunosuppressive regimens (Group 1, SRL) single-dose r-
ATG, TAC, SRL, and prednisone; (Group 2, EVR) single dose of r-ATG, TAC, EVR and 
prednisone; (Group 3, MCF) single dose of r-ATG, TAC, MPA and prednisone. 
The study was submitted to the local research ethics committee for approval and an 
informed consent form will be obtained from all patients. The study will be conducted 
within good clinical practice in accordance with the Declaration of Helsinki. Patients 
who meet the inclusion and exclusion criteria will be randomized within the first 24 
hours after transplantation, in a 1:1:1 ratio and stratified according to the type of 
donor (deceased or living). All patients will be followed for 12 months or until graft 
loss. 
 
2.2 Treatment Groups 
 
Grupo 1, SRL: r-ATG/SRL/TAC/Prednisone 
Patients will receive an initial dose of 0.05 mg/kg BID of TAC adjusted from day 3 to 
maintain a total blood concentration of TAC between 3-5 ng/mL. Patients will receive 
an initial dose of 3 mg QD sirolimus adjusted from day 3 to maintain a concentration 
between 4-8 ng/mL. 
 
Grupo 2, EVR: r-ATG/ EVR /TAC/Prednisone 
Patients will receive an initial dose of 0.05 mg/kg BID of TAC adjusted from day 3 to 
maintain a total blood concentration of TAC between 3-5 ng/mL. Patients will receive 
an initial dose of 1.5mg BID everolimus adjusted from day 3 to maintain a 
concentration between 4-8 ng/mL. 

 
 
 
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Grupo 3, MCF: r-ATG/Mycophenolate/TAC/Prednisone 
Patients will receive an initial dose of 0.1 mg/kg BID of TAC adjusted from day 4 
to maintain a total blood concentration of TAC between 5-10 ng/mL. Patients will 
receive fixed doses of mycophenolate (MMF, 1 g BID; MPS, 720 mg BID). 
 
2.3 Induction therapy 
All patients will receive 1 g of methylprednisolone before graft revascularization. 
All patients will receive a single dose of 3 mg/kg body weight of anti-thymocyte 
globulin administered intravenously over 6-8 hours, starting within the first 24 hours 
after graft revascularization. Pre-treatment will be performed with hydrocortisone and 
dipyrone, according to local practice. 
 
2.4 Maintenance therapy 
 
The first dose of all immunosuppressive drugs will be administered within the first 
24 hours after graft revascularization. 
Treatment group 
Drug 
Initial dose 
Concentration 
(ng/ml) 
Group 1, SRL (n=50) 
 
r-ATG 
3 mg/Kg IV day 1 
NA 
TAC 
0,05 mg/kg BID 
3-5 
Sirolimus 
3 mg QD 
4-8 
Group 2, EVR (n=50) 
 
r-ATG 
3 mg/Kg IV day 1 
NA 
TAC 
0,05 mg/kg BID 
3-5 
EVR 
1,5 mg BID 
4-8 
Group 3, MCF (n=50) 
 
r-ATG 
3 mg/Kg IV day 1 
NA 
TAC 
0,1 mg/kg BID 
5-10 
MMF ou 
MPS 
1000 mg BID 
720 mg BID 
NA 
NA 
 

 
 
 
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The primary use of other immunosuppressive drugs is prohibited. However, switching 
to another immunosuppressive drug is permitted both due to lack of efficacy 
(documented episodes of acute rejection) and the occurrence of adverse events. 
At the 6 month visit, all patients who are eligible, according to pre-established criteria, 
will simplify the TAC and EVR dosing schedule of BID for QD, maintaining the same 
daily dose in a single dose to achieve blood concentrations between 3 and 5 ng/ ml. 
 
2.5 Corticosteroids 
 
All patients will receive 0.5 mg/kg/day of prednisone with a maximum dose of 30 mg 
starting on day 1. Doses of prednisone will be reduced to 20 mg/day on day 7, 15 
mg/day on day 14, 10 mg /day on day 21 and 5 mg/day on day 30, which will be 
maintained for at least 12 months. 
 
2.6  Study rationale 
 
The use of a single dose of 3 mg/kg of anti-thymocyte globulin in induction therapy 
is currently standard in our institution, consistently providing an incidence of acute 
rejection of less than 10% at the end of the first year of transplantation. However, 
patients receiving this therapy and induction combined with standard maintenance 
therapy (TAC, mycophenolate, and prednisone) have a high incidence (60%) of CMV 
infection/disease. Using sirolimus or everolimus instead of mycophenolate may 
maintain efficacy for preventing acute rejection while reducing the incidence of CMV 
infection/disease. 
Adherence to immunosuppressive treatment is one of the factors with an 
important influence on long-term renal graft survival (9). The incidence of non-
adherence to treatment varies among different populations of kidney transplant 
recipients, reaching 60% in some cases. Constant education, technological facilities to 
alert the patient and simplification of medication dosage are strategies that can 
improve treatment adherence (10). 
Among the maintenance immunosuppressive regimens currently available to 
kidney transplant recipients, none offers the possibility of once-daily administration of 
all drugs to facilitate adherence to treatment. 

 
 
 
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2.7 Rationale of drug doses and concentrations 
 
Doses and concentrations of TAC combined with sirolimus or everolimus were 
based on prospective multicenter studies and also on the experience of our transplant 
center. Sirolimus was used in these studies as a loading dose because of its longer half-
life. Recent evidence suggests an association of this loading dose with a higher 
incidence of wound complications. The effectiveness of using r-ATG induction therapy 
may justify not using this loading dose. Sirolimus and everolimus belong to the same 
therapeutic class of immunosuppressants (mTOR inhibitors). A comparative analysis of 
published works suggests that the target concentrations of these two drugs are very 
close. Thus, the initial dose chosen for sirolimus and everolimus was 3 mg QD and the 
target residual blood concentrations will be similar, between 4-8 ng/ml. 
Although it is assumed that the use of SRL or EVR can provide similar results, some 
uncertainties justify the performance of this study. Due to its prolonged elimination 
half-life, SRL is administered as a single daily dose, usually after a loading dose (11). 
Recent studies suggest that this loading dose may be associated with the higher 
incidence of wound complications observed in the initial studies (12). Another 
important point is that the therapeutic concentration of SRL has not been clearly 
determined through prospective studies using current immunosuppression regimens 
(13). The evaluation of this regimen is therefore essential for its wider use, when 
indicated, especially considering the ease of dosage. 
Doses and concentrations of TAC and MPA correspond to those obtained in the 
largest prospective study in kidney transplant recipients and accepted as “standard of 
care” by regulatory agencies (14). 
Blood concentrations of SRL and EVR will be determined by HPLC and blood 
concentrations of TAC will be determined by chemiluminescence microparticle 
immunoassay (CMIA). 
 
2.8 Risks/benefits 
Sirolimus or everolimus regimens may reduce the incidence of viral infections, 
including CMV, herpes, and polyomavirus infection. In addition, there may be a 
reduction in the incidence of fungal and bacterial infections, a lower incidence of 

 
 
 
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diarrhea and myelotoxicity associated with the use of MPA. On the other hand, these 
regimens are associated with slow recovery of renal function, higher incidence of 
wound complications, edema, nephrotoxicity, proteinuria, and dyslipidemia. All of 
these adverse reactions are associated with disproportionately high concentrations of 
TAC and sirolimus or everolimus. 
 
3. Population 
A sample calculation was performed for each outcome to be analyzed in this 
study. The complete description is in section 10. “Statistical planning”. 
A total of 319 patients were included in the study. 
 
3.1  Inclusion criteria 
 
1. Recipients, adults of both genders, of the first standard living or deceased 
donor kidney transplant; 
2. Patients who agree to participate in the study and sign the informed consent 
form 
 
3.2 Exclusion criteria 
 
1. Recipients with a medical history of nephrotic syndrome or focal segmental 
glomerulosclerosis confirmed as the etiology of end-stage renal disease; 
2. Recipients with difficulty understanding chronic kidney disease and its treatment 
alternatives; 
3. 
Recipients 
with 
anticipated 
difficulty 
in 
adhering 
to 
treatment 
with 
immunosuppressive drugs; 
4. Retransplant recipients; 
5. Multi-organ receptors; 
6. Recipients with BMI>30 kg/m2; 
7. Deceased donor kidney recipients with KDPI > 80%; 
8. Deceased donor kidney recipients with cold ischemia time greater than 24 hours; 
9. Patients without specific antibodies against the donor. 

 
 
 
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10. Women of childbearing age who do not commit to using contraceptive methods 
(condoms or oral contraceptives). 
11. Patients using immunosuppressive therapy before transplantation, except for low-
dose prednisone; 
12. Patients with severe uncontrolled dyslipidemia; 
13. Patients who have a known contraindication for the administration of any of the 
immunosuppressive drugs provided for in this study; 
 
4. Randomization 
At the baseline visit, within 24 hours after vascular anastomosis, all eligible patients 
will be randomized using a numerical sequence, stratified by type of donor (deceased 
or living), generated by a computer program and placed in opaque envelopes. The 
open envelope, designated the treatment allocated to the patient, will be kept in your 
record. 
 
 
5. Prophylaxis against infections 
No pharmacological prophylaxis will be used against CMV infection. Preventive 
treatment will be carried out by monitoring virus replication detected by the 
antigenemia test. All patients will use oral nystatin for at least 30 days as prophylaxis 
of fungal infections. All patients will receive prophylaxis of parasitic infections with 
albendazole. All patients will use oral trimethoprim-sulfamethoxazole as prophylaxis of 
pneumocystis jirovecii or urinary tract infection. 
 
9. Definitions 
 
9.1 Delay Graft Function 
Delayed Garft Function will be defined as the need for dialysis during the first week 
after transplantation (with the exception of a single dialysis in the first 48 hours to 
treat hypervolemia and/or hyperkalemia after surgery. Patients with graft loss due to 
vascular thrombosis will be excluded. 
 
9.2 CMV infection and disease 

 
 
 
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9.2.1 CMV Infection: evidence of asymptomatic replication of CMV. 
 
9.2.2 CMV Disease: evidence of CMV infection with related symptoms. CMV disease 
can be categorized as a syndrome (fever, malaise, leukopenia, or 
thrombocytopenia) or as an invasive disease with histological evidence. 
 
 
9.2.3 Recurrent CMV disease/infection: defined as a new episode of CMV infection 
after documented effective previous treatment (2 weekly negative antigenemia 
tests). 
 
9.2.4 CMV replication: will be confirmed by detection of CMV pp65 antigen by 
indirect immunofluorescence in peripheral blood leukocytes. The 
diagnosis of viral replication is confirmed by the presence of 10 or more 
positive cells per 200,000 peripheral blood leukocytes in asymptomatic 
patients or any number of positive cells in the presence of typical 
symptoms or in recipients with negative serology for CMV. 
 
 
9.2.5 Preemptive strategy: monitoring of CMV replication will be performed every 
15 days between the third and 12 weeks after transplantation. Additional 
monitoring will be performed for 12 weeks after treatment for acute rejection. 
 
9.2.6 Treatment of CMV disease/infection: Patients will receive standard 
intravenous ganciclovir (5 mg/kg every 12 hours) corrected for renal function as 
per package insert recommendations. Monitoring of CMV replication will be 
carried out weekly. The duration of treatment will be extended by one week 
after the first negative antigenemia test. Consequently, the minimum duration 
of treatment will be 14 days. The duration of treatment for patients with 
invasive disease will be at least 21 days, being extended in the presence of a 
positive antigenemia test. 
 

 
 
 
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10 Statistical planning 
 
10.1 
Sample size - main study 
 
Primary outcome: cytomegalovirus infection or disease 
For the primary outcome of cytomegalovirus infection, we calculated the sample 
required to show superiority of the experimental groups (EVR and SRL) over the 
control (MPA). For this calculation, we considered an incidence of 72% in the MPA 
group and an expected reduction of 50% (to 36%) in the experimental groups. For a 
margin of superiority of 0% and power of 90%, the total number of patients would be 
42 in each group, considering 20% drop outs. 
 
 
11 Referece 
1. 
Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, et al. 
Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant. 
2006;6(5 Pt 2):1111-31. 
2. 
Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. 
Reduced exposure to calcineurin inhibitors in renal transplantation.  N Engl J Med. 357. 
United States: 2007 Massachusetts Medical Society.; 2007. p. 2562-75. 
3. 
Hellemans R, Bosmans JL, Abramowicz D. Induction Therapy for Kidney 
Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies? Am 
J Transplant. 2017;17(1):22-7. 
4. 
Webster AC, Ruster LP, McGee R, Matheson SL, Higgins GY, Willis NS, et al. 
Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database 
Syst Rev. 2010(1):Cd003897. 
5. 
Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, et al. 
Updated international consensus guidelines on the management of cytomegalovirus in 
solid-organ transplantation. Transplantation. 2013;96(4):333-60. 
6. 
Song AT, Abdala E, Bonazzi PR, Bacchella T, Machado MC. Does mycophenolate 
mofetil increase the risk of cytomegalovirus infection in solid organ transplant 
recipients?--A mini-review. Braz J Infect Dis. 2006;10(2):132-8. 

 
 
 
12
7. 
Andrassy J, Hoffmann VS, Rentsch M, Stangl M, Habicht A, Meiser B, et al. Is 
cytomegalovirus prophylaxis dispensable in patients receiving an mTOR inhibitor-based 
immunosuppression? a systematic review and meta-analysis. Transplantation. 
2012;94(12):1208-17. 
8. 
Tedesco-Silva H, Felipe C, Ferreira A, Cristelli M, Oliveira N, Sandes-Freitas T, et 
al. Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients 
Receiving 
Everolimus 
and 
Reduced 
Tacrolimus 
Doses. 
Am 
J 
Transplant. 
2015;15(10):2655-64. 
9. 
Shihab F, Christians U, Smith L, Wellen JR, Kaplan B. Focus on mTOR inhibitors 
and tacrolimus in renal transplantation: pharmacokinetics, exposure-response 
relationships, and clinical outcomes. Transpl Immunol. 2014;31(1):22-32. 
10. 
Cooper M, Wiseman AC, Zibari G, McCague K, Kim Y, Geissler F, et al. Wound 
events in kidney transplant patients receiving de novo everolimus: a pooled analysis of 
three randomized controlled trials. Clin Transplant. 2013;27(6):E625-35. 
11. 
Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events 
associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28(3):126-33. 
1. 
Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, et al. 
Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant. 
2006;6(5 Pt 2):1111-31. 
2. 
Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. 
Reduced exposure to calcineurin inhibitors in renal transplantation.  N Engl J Med. 357. 
United States: 2007 Massachusetts Medical Society.; 2007. p. 2562-75. 
3. 
Hellemans R, Bosmans JL, Abramowicz D. Induction Therapy for Kidney 
Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies? Am 
J Transplant. 2017;17(1):22-7. 
4. 
Webster AC, Ruster LP, McGee R, Matheson SL, Higgins GY, Willis NS, et al. 
Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database 
Syst Rev. 2010(1):Cd003897. 
5. 
Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, et al. 
Updated international consensus guidelines on the management of cytomegalovirus in 
solid-organ transplantation. Transplantation. 2013;96(4):333-60. 

 
 
 
13
6. 
Song AT, Abdala E, Bonazzi PR, Bacchella T, Machado MC. Does mycophenolate 
mofetil increase the risk of cytomegalovirus infection in solid organ transplant 
recipients?--A mini-review. Braz J Infect Dis. 2006;10(2):132-8. 
7. 
Shihab FS, Cibrik D, Chan L, Kim YS, Carmellini M, Walker R, et al. Association of 
clinical events with everolimus exposure in kidney transplant patients receiving 
reduced cyclosporine. Clin Transplant. 2013;27(2):217-26. 
8. 
Tedesco-Silva H, Felipe C, Ferreira A, Cristelli M, Oliveira N, Sandes-Freitas T, et 
al. Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients 
Receiving 
Everolimus 
and 
Reduced 
Tacrolimus 
Doses. 
Am 
J 
Transplant. 
2015;15(10):2655-64. 
9. 
Prendergast MB, Gaston RS. Optimizing medication adherence: an ongoing 
opportunity to improve outcomes after kidney transplantation. Clin J Am Soc Nephrol. 
2010;5(7):1305-11. 
10. 
Patzer RE, Serper M, Reese PP, Przytula K, Koval R, Ladner DP, et al. Medication 
understanding, non-adherence, and clinical outcomes among adult kidney transplant 
recipients. Clin Transplant. 2016;30(10):1294-305. 
11. 
Brennan DC, Aguado JM, Potena L, Jardine AG, Legendre C, Saeemann MD, et 
al. Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence 
and potential mechanisms. Reviews in Medical Virology. 2013;23(2):97-125. 
12. 
Weng FL, Israni AK, Joffe MM, Hoy T, Gaughan CA, Newman M, et al. Race and 
electronically measured adherence to immunosuppressive medications after deceased 
donor renal transplantation. J Am Soc Nephrol. 2005;16(6):1839-48. 
13. 
Briggs AH, Weinstein MC, Fenwick EA, Karnon J, Sculpher MJ, Paltiel AD, et al. 
Model parameter estimation and uncertainty: a report of the ISPOR-SMDM Modeling 
Good Research Practices Task Force--6. Value Health. 2012;15(6):835-42. 
14. 
Ekberg H, Bernasconi C, Tedesco-Silva H, Vítko S, Hugo C, Demirbas A, et al. 
Calcineurin inhibitor minimization in the Symphony study: observational results 3 years 
after transplantation. Am J Transplant. 2009;9(8):1876-85. 
15. 
Baraldo M, Furlanut M. Chronopharmacokinetics of ciclosporin and tacrolimus. 
Clin Pharmacokinet. 2006;45(8):775-88. 
16. 
Park SI, Felipe CR, Pinheiro-Machado PG, Garcia R, Tedesco-Silva H, Medina-
Pestana JO. Circadian and time-dependent variability in tacrolimus pharmacokinetics. 
Fundam Clin Pharmacol. 2007;21(2):191-7. 

 
 
 
14
17. 
Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of 
tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53. 
 
19. Niels O.S. Camara, Joilson O. Martins, Richardt G. Landgraf and Sonia Jancar. 
Emerging roles for eicosanoids in renal diseases. Current Opinion in Nephrology and 
Hypertension 2009, 18:21–27 
18. Jelena Klawitter, Jost Klawitter, Kim McFann, Alexander T. Pennington, Kaleab Z. Abebe, 
Godela rosnahan,Melissa A. Cadnapaphornchai, Michel Chonchol,Berenice Gitomer,Uwe 
Christians, and Robert W. Schrier. Bioactive lipid mediators in polycystic kidney disease. J Lipid 
Res. 2014 Jun; 55(6): 1139–1149. 
20. Katabathina V, Menias CO, Pickhardt P, Lubner M, Prasad SR. Complications of 
Immunosuppressive Therapy in Solid Organ Transplantation. Radiol Clin North Am 
[Internet]. Elsevier Inc; 2016;54(2):303–19. 
21. Weng RR, Foster CE, Hsieh LL, Patel PR. Oral ulcers associated with mycophenolate 
mofetil use in a renal transplant recipient. Am J Heal Pharm. 2011;68(7):585–8.