Published online Aug 28, 2014. doi: 10.3748/wjg.v20.i32.11356
Revised: March 15, 2014
Accepted: April 21, 2014
Published online: August 28, 2014
AIM: To determine whether low-dose tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is a safe approach to decrease the incidence of chronic kidney disease (CKD) in liver transplantation (LT) recipients.
METHODS: We analyzed the medical records of 689 patients who underwent LT between March 1999 and December 2012 in a single Chinese center. Immunosuppression was initiated with a calcineurin inhibitor (TAC or CSA) and prednisone with or without MMF. CKD is defined by the glomerular filtration rate (GFR), estimated by an abbreviated Modification of Diet in Renal Disease formula, < 60 mL/min per 1.73 m2 for at least 3 consecutive months after LT. Individuals with TAC trough concentrations ≤ 8 ng/mL at 3 mo after LT were defined as the low-dose group. The incidence of CKD within 5 years was compared between the TAC group and the CSA group, as well as between four subgroups (low-dose and high-dose TAC groups with or without MMF).
RESULTS: No difference regarding the occurrence of pre-LT renal dysfunction or that of post-LT rejection was found between the TAC and CSA groups or between the four subgroups. With a definition of GFR < 60 mL/min per 1.73 m2, the overall incidence of CKD was significantly higher in the CSA group than in the TAC group. The incidence of CKD in the low-dose TAC + MMF group (7.7%) was significantly lower than that observed in the low-dose TAC group (15.9%), high-dose TAC group (24.6%) and high-dose TAC + MMF group (18.5%). The cumulative 1-, 3- and 5-year incidence rates of CKD were 12.7%, 14.5% and 16.7%, respectively. The cumulative 5-year survival rates were 61.7% and 82.2% in patients with or without CKD, respectively.
CONCLUSION: In LT patients, the choice of immunosuppressive therapy appears to affect renal function and patient survival.
Core tip: Calcineurin inhibitor nephrotoxicity has been proposed to have a central role in chronic kidney disease, which has become a leading cause of long-term morbidity and mortality after liver transplantation. This study was conducted in 689 consecutive liver transplantation recipients and suggested that the choice of the immunosuppression therapy should be low-dose tacrolimus combined with mycophenolate mofetil, as this treatment was associated with better renal function and a higher patient survival rate.
- Citation: Hao JC, Wang WT, Yan LN, Li B, Wen TF, Yang JY, Xu MQ, Zhao JC, Wei YG. Effect of low-dose tacrolimus with mycophenolate mofetil on renal function following liver transplantation. World J Gastroenterol 2014; 20(32): 11356-11362
- URL: https://www.wjgnet.com/1007-9327/full/v20/i32/11356.htm
- DOI: https://dx.doi.org/10.3748/wjg.v20.i32.11356
The use of the calcineurin inhibitors (CNIs) cyclosporine A (CSA) and tacrolimus (TAC) in liver transplantation (LT) has greatly increased recipient survival rates and reduced graft rejection rates[1]. However, CNI nephrotoxicity has been proposed to have a central role in chronic kidney disease (CKD) after LT[2-4]. CKD has become a leading cause of long-term morbidity and mortality[5]. Ojo et al[5] reported that 18% of 36849 LT recipients had chronic renal dysfunction defined as a glomerular filtration rate (GFR) < 29 mL/min per square meter 5 years after LT.
Although the different impacts of TAC and CSA on renal function remains controversial, there has been substantial evidence that TAC has lower nephrotoxicity potential than CSA, especially in kidney transplant recipients. Numerous studies have shown that recipients treated with TAC display better renal function than those who receive CSA[6-9]. However, Alghamdi et al[10] found no difference in the mean levels of serum creatinine between the CSA and TAC groups, but this effect remains inconclusive in LT patients[11,12].
The most direct strategies to prevent CNI nephrotoxicity are avoidance and withdrawal of the drug. However, the exclusion of CNIs from immunosuppressive regimens does not preserve allograft function due to inadequate acute rejection prophylaxis by other immunosuppressive regimens[13-16]. Herein, novel CNI minimization protocols, in which the doses of cyclosporine or tacrolimus are adjusted to lower target levels, were conducted to balance potent immunosuppression and reduce CNI exposure. Morard et al[17] showed that independent risk factors associated with impaired renal function were trough levels of CSA ≥ 150 ng/mL or TAC ≥ 10 ng/mL at 1 year and CSA ≥ 100 ng/mL or TAC ≥ 8 ng/mL at 5 years. Our previous study showed that groups with ideal trough concentrations (CSA trough concentrations ≤ 150 ng/mL, TAC trough concentrations ≤ 8 ng/mL) had a significantly lower incidence of CKD[18]. A recent meta-analysis of 64 studies demonstrated that lower trough concentrations of TAC (6-10 ng/mL during the first month) had no significant influence on acute rejection and that TAC would be more appropriate after LT[19].
Immunosuppressive drugs without renal side effects have been increasingly used as CNI-sparing agents. Mycophenolate mofetil (MMF) is a non-nephrotoxic drug that inhibits the proliferation of T and B lymphocytes and has proven efficacy in the field of LT[20]. Substantial evidence has been found to suggest that MMF induction and maintenance used in conjunction with CNI following LT resulted in a significant improvement in renal function[21-25].
The aims of the present study were to determine whether TAC yields a lower incidence of CKD than CSA in recipients undergoing LT, as well as to investigate whether the use of reduced-dose TAC combined with MMF is a relatively safe approach to decrease the incidence of CKD.
In this retrospective study, data from the clinical records of 940 consecutive patients who underwent LT between March 1999 and December 2012 in a single Chinese center were analyzed. The observation period ended on August 31, 2013, or at the time of patient death. Recipients who were followed up for less than 3 mo or died within 3 mo after transplantation, as well as those younger than 18 years, were excluded from the current study. All liver grafts were obtained from brain-dead or living donors. Living and deceased donations were voluntary in all cases, were approved by the West China Hospital Ethics Committee and were in accord with the ethical guidelines of the Declaration of Helsinki.
Renal function was assessed by the estimated GFR (eGFR) obtained using the abbreviated Modification of Diet in Renal Disease formula: eGFR = 186 × creatinine (mg/dL)-1.154× (age)-0.203× (0.742 if female)[26]. CKD was defined as having a GFR < 60 mL/min per 1.73 m2 for at least 3 consecutive months after LT. Renal dysfunction before LT was also defined as having an eGFR < 60 mL/min per 1.73 m2. Acute kidney injury (AKI) was defined as a > 25% decrease in GFR in the first post-operative week compared with the pre-operative level[27].
Acute rejection (AR) and chronic rejection (CR) were confirmed by liver biopsy. Mayo end-stage liver disease scores were calculated for each patient.
Immunosuppression was initiated with a CNI (TAC or CSA) and prednisone with or without MMF. The initial dose of CNI was 0.05-0.10 mg/kg daily for TAC and 5-10 mg/kg daily for CSA. The dose of MMF was determined individually and ranged from 1.0-1.5 g/d. At our center, patients were only administered MMF during the early phase after transplantation when they were diagnosed with hypertension or diabetes mellitus; however, all recipients in the late post-transplant period were administered MMF unless severe gastrointestinal side effects or myelosuppression occurred. Prednisone was generally discontinued within 3 mo after transplantation.
CNI trough concentrations were checked daily for the first week, weekly for the next three weeks during the first post-operative month, monthly within 3 mo and every 3 mo thereafter. The ideal serum trough level of CNI was 6-8 ng/mL for TAC and 120-150 ng/mL for CSA at 3 mo after operation. We classified patients with a TAC trough concentration ≤ 8 ng/mL at 3 mo after LT as the low-dose group. Liver function was monitored intensely while adjusting the CNI dose. If AR occurred, the previous dosage was restarted with an increased prednisone dosage or high-dose methylprednisolone administration. Dose reduction was carefully and slowly carried out. A trough level of 4-6 ng/mL for TAC and 80-120 ng/mL for CSA one year after transplantation was expected to achieve stable liver function.
Numerical data are presented as the mean ± SD or as the median. The χ2 test or Fisher’s exact test was used to compare categorical variables. Continuous data were compared using the independent t test if data were normally distributed or using the rank-sum test if data were non-normally distributed. All analyses were performed using SPSS 22.0 statistical software (IBM Corporation, Armonk, NY). P < 0.05 was considered statistically significant.
The medical records of 689 patients who met the inclusion criteria, including 575 males and 114 females with a mean age of 44.94 years, were retrospectively reviewed. The median follow-up duration was 24 (3-120) mo. The two most common primary diagnoses for recipients were tumors and cirrhosis, with 344 (49.9%) and 232 (33.7%) patients, respectively. More than 80% of cases were found to be hepatitis B virus (HBV)-related. The deceased donor transplantation rate was 74.2%. TAC group patients were divided into two groups based on the critical ideal trough concentration of ≤ 8 ng/mL at 3 mo after transplantation. Furthermore, four subgroups were created depending on whether MMF therapy was adopted.
The eGFR was calculated after each patient visit. Once the criterion for CKD was met, the patient was registered in the CKD group. As shown in Figure 1, 16.7% of the entire patient population (115 cases) developed CKD during the 5-year follow-up.
No differences were found in renal dysfunction before LT or in AKI, AR and CR after LT between the TAC and CSA groups (Table 1) as well as between the four TAC subgroups (low-dose and high dose TAC with or without MMF, Table 2). The cumulative incidence of CKD at 3, 6, 12, 24, 36, 48 and 60 mo was 15.0%, 16.9%, 20.0%, 23.1%, 25.0% and 26.3%, respectively, in the CSA group and 4.5%, 7.4%, 10.2%, 11.3%, 11.9%, 13.2% and 13.8%, respectively, in the TAC group (Figure 1A, P < 0.05). The intragroup analysis of TAC showed that the low-dose TAC with MMF group had a significantly lower incidence of CKD at these times compared with the other three groups (2.6%, 4.7%, 6%, 7.2%, 7.2%, 7.2% and 7.7%, respectively; Figure 1B, P < 0.05).
| Total (n = 689) | TAC (n = 529) | CSA (n = 160) | P value | |
| Age (yr) | 44.94 ± 9.68 | 44.70 ± 9.25 | 45.73 ± 10.98 | NS |
| Gender (male/female) | 575/114 | 448/81 | 127/33 | NS |
| Donor type (DDLT/LDLT) | 511/178 | 368/161 | 143/17 | < 0.001 |
| MELD score | 13.77 ± 7.77 | 13.54 ± 7.96 | 14.54 ± 7.07 | NS |
| Pre-LT renal dysfunction | 61 (8.9) | 46 (8.7) | 15 (9.4) | NS |
| Post-LT AKI | 108 (15.7) | 80 (15.1) | 28 (17.5) | NS |
| Post-LT AR | 78 (11.3) | 53 (10.0) | 25 (15.6) | NS |
| Post-LT CR | 18 (2.6) | 13 (2.5) | 5 (3.1) | NS |
| Primary diagnosis | NS | |||
| Tumors | 344 (49.9) | 265 (50.1) | 79 (49.4) | |
| Cirrhosis | 232 (33.7) | 182 (34.4) | 50 (31.3) | |
| Chronic active hepatitis | 54 (7.8) | 36 (6.8) | 18 (11.3) | |
| Others | 59 (8.6) | 46 (8.7) | 13 (8.1) | |
| Viral infection | NS | |||
| HBV infection | 564 (81.9) | 435 (82.2) | 129 (80.6) | |
| HCV infection | 9 (1.3) | 8 (1.5) | 1 (0.6) |
| Total (n = 529) | Low-dose TAC (n = 113) | Low-dose TAC with MMF (n = 235) | High-dose TAC (n = 61) | High-dose TAC with MMF (n = 120) | P value | |
| Age (yr) | 44.00 ± 9.25 | 45.00 ± 9.61 | 44.86 ± 9.21 | 42.93 ± 8.83 | 44.98 ± 9.20 | NS |
| Gender | 448/81 | 95/18 | 200/35 | 51/10 | 102/18 | NS |
| Donor type | 368/161 | 102/11 | 143/92 | 49/12 | 74/46 | < 0.001 |
| MELD score | 13.54 ± 7.96 | 15.03 ± 8.34 | 13.15 ± 7.85 | 13.48 ± 6.59 | 12.94 ± 8.37 | NS |
| Renal dysfunction pre-LT | 46 (8.7) | 15 (13.3) | 16 (6.8) | 8 (13.1) | 7 (5.8) | NS |
| Post-LT AKI | 80 (15.1) | 22 (19.5) | 33 (14.0) | 11 (18.0) | 14 (11.7) | NS |
| Post-LT AR | 53 (10.0) | 15 (13.3) | 18 (7.7) | 10 (16.4) | 10 (8.3) | NS |
| Post-LT CR | 13 (2.5) | 3 (2.7) | 5 (2.1) | 2 (3.2) | 3 (2.5) | NS |
| Primary diagnosis | NS | |||||
| Tumors | 265 (50.1) | 61 (54.0) | 107 (45.5) | 35 (57.4) | 62 (51.7) | |
| Cirrhosis | 182 (34.4) | 39 (34.5) | 89 (37.9) | 17 (27.9) | 37 (30.8) | |
| Chronic active hepatitis | 36 (6.8) | 9 (8.0) | 12 (5.1) | 4 (6.6) | 11 (9.2) | |
| Others | 46 (8.7) | 4 (3.5) | 27 (11.5) | 5 (8.2) | 10 (8.3) | |
| Viral infection | NS | |||||
| HBV infection | 435 (82.2) | 95 (84.1) | 191 (81.3) | 48 (78.7) | 101 (84.2) | |
| HCV infection | 8 (1.5) | 2 (1.8) | 6 (2.6) | 0 | 0 |
The cumulative survival rates at 5 years after LT in patients with and without CKD were 61.7% and 82.2%, respectively (log-rank test, P < 0.05) (Figure 2).
The present study demonstrated a cumulative incidence of CKD of 12.5% within 1 year, 14.5% at 3 years and 16.7% at 5 years after LT. We observed that TAC supported better renal function than CSA, especially when used at a low dose and in combination with MMF. This combined regimen showed the most stable long-term outcome, with a CKD incidence of only 7.7% at 5 years after LT. We also confirmed that CKD yielded a lower patient survival rate.
All of the comparisons made before transplantation were similar, even if a difference appeared concerning donor type. These similarities were most likely due to the chronological aspect of the study. In our previous research, we confirmed that donor type had no significant impact on renal dysfunction[18].
There is substantial evidence that TAC has a lower nephrotoxicity potential than CSA. Animal studies have demonstrated that the vasoconstrictive effect of TAC is weaker than that of CSA[28-30], and this effect was also apparent in humans[31,32]. Moreover, the fibrogenic potential of TAC appears to be lower than that of CSA[33], although these results could not be confirmed in a more recent study[34]. For nonrenal solid organ transplantation, there have been single and multicenter studies, as well as registry analyses, that demonstrate the benefit of TAC over CSA with regard to renal function[5,35-37]. However, other studies exist that do not report this benefit of TAC over CSA[38].
In contrast to CSA, for which no dose-finding studies were performed before its introduction into clinical practice, extensive studies on TAC were performed before its introduction, and these demonstrated significant correlations between concentration and rejection and between concentration and toxicity[39]. To avoid CNI nephrotoxicity, minimizing CNI levels may be a better option, but it has become clear that the increased risk of allograft rejection could negate these positive effects. The positive effects observed following the introduction of MMF, which does not interfere with CNI actions or cause renal toxicity, as a rescue treatment for renal dysfunction due to CNI toxicity have been reported in several studies[40-42]. Moreover, MMF could have nephroprotective properties. Romero et al[43] noted that MMF prevented progressive renal failure in rats that underwent 5/6 renal ablation and hypothesized that MMF has an antiproliferative effect. In fact, in various cell lines (e.g., smooth muscle cells, renal tubular cells and mesangial cells), MMF reduced or even abrogated proliferation in response to proliferative stimuli[44]. These same effects on endothelial cells may counteract the harmful vascular effects of CNI and explain the beneficial effects of MMF in the prevention and treatment of CNI toxicity apart from the effect of a CNI dose decrease. As a result, the lower decrease in the GFR observed in patients receiving MMF may not be due only to the CNI dose reduction.
In conclusion, we showed that in LT patients, the optimal calcineurin inhibitor is low-dose TAC combined with MMF, as this treatment was associated with a better long-term GFR (10 mL/min per 1.73 m2), thereby decreasing renal toxicity, and a higher patient survival rate.
We thank the Chinese Liver Transplant Registry (http://www.cltr.org) for providing the data.
Calcineurin inhibitors (CNI), since their introduction in the 1980s, have been the cornerstone of maintenance immunosuppressive regimens in liver transplantation. The use of CNI has substantially decreased the risk of acute rejection and improved short-term outcomes. However, CNI is associated with severe adverse effects, such as nephrotoxicity, dyslipidemia and hypertension especially in cyclosporine A (CSA). Recent studies showed that tacrolimus is preferred over CSA as an immunosuppressive agent. Low dose administration of immunosuppressive agents, such as tacrolimus, might reduce the risk of graft rejection, as well as cut down the cost of immunosuppressive therapy. However, correlation between the dosage of tacrolimus and the associated side effects and survival rates in liver transplant (LT) patients is largely unknown.
Tacrolimus (TAC) has been proved with a less nephrotoxicity than CSA as well as mycophenolate mofetil (MMF), which have been used commonly in transplantations. In the area of prevention of chronic kidney disease (CKD) after LT, the research hotspot is how to balance the potent immunosuppression and less CNI exposure.
This article focused on developing and validating a low-dose tacrolimus combined with MMF as a better choice of immunosuppression. The study included 689 consecutive liver transplantation recipients. Glomerular filtration rate, estimated by an abbreviated modification of diet in renal disease formula, suggested CKD when it is lower than 60 mL/min per 1.73 m2 for at least 3 consecutive months after LT. TAC trough concentrations ≤ 8 ng/mL at 3 mo after LT was defined as low-dose group. Incidence of CKD within 5 years was compared between TAC group and CSA group, as well as among four subgroups (low-dose and high-dose TAC groups with or without MMF). This study was with a high volume cohort and suggested that the choice of the immunosuppression should be low-dose TAC combined with MMF because it was associated with a better renal function and a higher patient survival rate.
The study results suggest that the choice of immunosuppressive therapy appears to affect renal function and patient survival in LT.
Tacrolimus (trade name Prograf) is a product of the bacterium Streptomyces tsukubaensis. It is a macrolide lactone and acts by inhibiting calcineurin. The drug is used primarily in liver and kidney transplantations, although in some clinics it is used in heart, lung, and heart/lung transplantations. It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects. CKD, also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are non-specific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis. It is differentiated from acute kidney disease in that the reduction in kidney function must be present for over 3 mo.
This is a good retrospective study in which the authors analyzed the effect of low-dose tacrolimus with mycophenolate mofetil on the incidence of chronic kidney disease following liver transplantation. The results are interesting and suggest that the choice of the immunosuppression appears to affect renal function and patient survival following LT.
P- Reviewer: Mathis AS S- Editor: Gou SX L- Editor: Ma JY E- Editor: Wang CH
| 1. | Hong JC, Kahan BD. Immunosuppressive agents in organ transplantation: past, present, and future. Semin Nephrol. 2000;20:108-125. [PubMed] [Cited in This Article: ] |
| 2. | Ojo AO. Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol. 2007;27:498-507. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 88] [Cited by in F6Publishing: 76] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
| 3. | Wilkinson A, Pham PT. Kidney dysfunction in the recipients of liver transplants. Liver Transpl. 2005;11 Suppl 2:S47-S51. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 51] [Cited by in F6Publishing: 51] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
| 4. | Bahirwani R, Reddy KR. Outcomes after liver transplantation: chronic kidney disease. Liver Transpl. 2009;15 Suppl 2:S70-S74. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 67] [Cited by in F6Publishing: 71] [Article Influence: 4.7] [Reference Citation Analysis (0)] |
| 5. | Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931-940. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1703] [Cited by in F6Publishing: 1588] [Article Influence: 75.6] [Reference Citation Analysis (0)] |
| 6. | Marcard T, Ivens K, Grabensee B, Willers R, Helmchen U, Rump LC, Blume C. Early conversion from cyclosporine to tacrolimus increases renal graft function in chronic allograft nephropathy at BANFF stages I and II. Transpl Int. 2008;21:1153-1162. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 8] [Cited by in F6Publishing: 9] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 7. | Krämer BK, Del Castillo D, Margreiter R, Sperschneider H, Olbricht CJ, Ortuño J, Sester U, Kunzendorf U, Dietl KH, Bonomini V. Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results. Nephrol Dial Transplant. 2008;23:2386-2392. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 46] [Cited by in F6Publishing: 43] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
| 8. | Shihab FS, Waid TH, Conti DJ, Yang H, Holman MJ, Mulloy LC, Henning AK, Holman J, First MR. Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF Study. Transplantation. 2008;85:1261-1269. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 44] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
| 9. | Gonzalez Molina M, Morales JM, Marcen R, Campistol JM, Oppenheimer F, Serón D, Gil-Vernet S, Capdevila L, Andrés A, Lampreave I. Renal function in patients with cadaveric kidney transplants treated with tacrolimus or cyclosporine. Transplant Proc. 2007;39:2167-2169. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 4] [Cited by in F6Publishing: 4] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
| 10. | Alghamdi S, Nabi Z, Skolnik E, Alkorbi L, Albaqumi M. Cyclosporine versus tacrolimus maintenance therapy in renal transplant. Exp Clin Transplant. 2011;9:170-174. [PubMed] [Cited in This Article: ] |
| 11. | Lucey MR, Abdelmalek MF, Gagliardi R, Granger D, Holt C, Kam I, Klintmalm G, Langnas A, Shetty K, Tzakis A. A comparison of tacrolimus and cyclosporine in liver transplantation: effects on renal function and cardiovascular risk status. Am J Transplant. 2005;5:1111-1119. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 71] [Cited by in F6Publishing: 73] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 12. | Charco R, Cantarell C, Castells LI, Bilbao I, Hidalgo E, Capdevila L, Margarit C. Changes in renal function in long-term survivors of liver transplantation: a comparison between cyclosporine microemulsion and tacrolimus therapy. Transplant Proc. 2002;34:1548-1549. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Cited by in F6Publishing: 1] [Article Influence: 0.0] [Reference Citation Analysis (0)] |
| 13. | Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, Margreiter R, Hugo C, Grinyó JM, Frei U. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562-2575. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1362] [Cited by in F6Publishing: 1296] [Article Influence: 76.2] [Reference Citation Analysis (0)] |
| 14. | Ekberg H, Grinyó J, Nashan B, Vanrenterghem Y, Vincenti F, Voulgari A, Truman M, Nasmyth-Miller C, Rashford M. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant. 2007;7:560-570. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 211] [Cited by in F6Publishing: 219] [Article Influence: 12.9] [Reference Citation Analysis (0)] |
| 15. | Srinivas TR, Meier-Kriesche HU. Minimizing immunosuppression, an alternative approach to reducing side effects: objectives and interim result. Clin J Am Soc Nephrol. 2008;3 Suppl 2:S101-S116. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 103] [Cited by in F6Publishing: 107] [Article Influence: 6.7] [Reference Citation Analysis (0)] |
| 16. | Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant. 2008;22:1-15. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 14] [Cited by in F6Publishing: 61] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 17. | Morard I, Mentha G, Spahr L, Majno P, Hadengue A, Huber O, Morel P, Giostra E. Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels. Clin Transplant. 2006;20:96-101. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 52] [Cited by in F6Publishing: 55] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
| 18. | Shao ZY, Yan LN, Wang WT, Li B, Wen TF, Yang JY, Xu MQ, Zhao JC, Wei YG. Prophylaxis of chronic kidney disease after liver transplantation--experience from west China. World J Gastroenterol. 2012;18:991-998. [PubMed] [DOI] [Cited in This Article: ] [Cited by in CrossRef: 11] [Cited by in F6Publishing: 11] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 19. | Rodríguez-Perálvarez M, Germani G, Darius T, Lerut J, Tsochatzis E, Burroughs AK. Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. Am J Transplant. 2012;12:2797-2814. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 120] [Cited by in F6Publishing: 119] [Article Influence: 9.9] [Reference Citation Analysis (0)] |
| 20. | Fisher RA, Stone JJ, Wolfe LG, Rodgers CM, Anderson ML, Sterling RK, Shiffman ML, Luketic VA, Contos MJ, Mills AS. Four-year follow-up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation. Clin Transplant. 2004;18:463-472. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 47] [Cited by in F6Publishing: 48] [Article Influence: 2.4] [Reference Citation Analysis (0)] |
| 21. | Barkmann A, Nashan B, Schmidt HH, Böker KH, Emmanouilidis N, Rosenau J, Bahr MJ, Hoffmann MW, Manns MP, Klempnauer J. Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil. Transplantation. 2000;69:1886-1890. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 89] [Cited by in F6Publishing: 92] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 22. | Raimondo ML, Dagher L, Papatheodoridis GV, Rolando N, Patch DW, Davidson BR, Rolles K, Burroughs AK. Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Transplantation. 2003;75:186-190. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 66] [Cited by in F6Publishing: 65] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
| 23. | Cantarovich M, Tzimas GN, Barkun J, Deschênes M, Alpert E, Tchervenkov J. Efficacy of mycophenolate mofetil combined with very low-dose cyclosporine microemulsion in long-term liver-transplant patients with renal dysfunction. Transplantation. 2003;76:98-102. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 64] [Cited by in F6Publishing: 66] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
| 24. | Reich DJ, Clavien PA, Hodge EE. Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results. Transplantation. 2005;80:18-25. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 75] [Cited by in F6Publishing: 76] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
| 25. | Haywood S, Abecassis M, Levitsky J. The renal benefit of mycophenolate mofetil after liver transplantation. Clin Transplant. 2011;25:E88-E95. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in F6Publishing: 11] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
| 26. | Gonwa TA, Jennings L, Mai ML, Stark PC, Levey AS, Klintmalm GB. Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations. Liver Transpl. 2004;10:301-309. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 258] [Cited by in F6Publishing: 271] [Article Influence: 13.6] [Reference Citation Analysis (0)] |
| 27. | Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56:1310-1318. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 156] [Cited by in F6Publishing: 335] [Article Influence: 19.7] [Reference Citation Analysis (0)] |
| 28. | Bagnis C, Deray G, Dubois M, Adabra Y, Jacquiaud C, Jaudon MC, Jacobs C. Comparative acute nephrotoxicity of FK-506 and ciclosporin in an isolated in situ autoperfused rat kidney model. Am J Nephrol. 1997;17:17-24. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 27] [Cited by in F6Publishing: 29] [Article Influence: 1.1] [Reference Citation Analysis (0)] |
| 29. | Epstein A, Beall A, Wynn J, Mulloy L, Brophy CM. Cyclosporine, but not FK506, selectively induces renal and coronary artery smooth muscle contraction. Surgery. 1998;123:456-460. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 25] [Cited by in F6Publishing: 25] [Article Influence: 1.0] [Reference Citation Analysis (0)] |
| 30. | Gardiner SM, March JE, Kemp PA, Fallgren B, Bennett T. Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats. Br J Pharmacol. 2004;141:634-643. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 41] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
| 31. | Klein IH, Abrahams A, van Ede T, Hené RJ, Koomans HA, Ligtenberg G. Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation. 2002;73:732-736. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 4] [Cited by in F6Publishing: 4] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
| 32. | Nankivell BJ, Chapman JR, Bonovas G, Gruenewald SM. Oral cyclosporine but not tacrolimus reduces renal transplant blood flow. Transplantation. 2004;77:1457-1459. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 59] [Cited by in F6Publishing: 63] [Article Influence: 3.2] [Reference Citation Analysis (0)] |
| 33. | Jain S, Bicknell GR, Nicholson ML. Tacrolimus has less fibrogenic potential than cyclosporin A in a model of renal ischaemia-reperfusion injury. Br J Surg. 2000;87:1563-1568. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 48] [Cited by in F6Publishing: 52] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
| 34. | Roos-van Groningen MC, Scholten EM, Lelieveld PM, Rowshani AT, Baelde HJ, Bajema IM, Florquin S, Bemelman FJ, de Heer E, de Fijter JW. Molecular comparison of calcineurin inhibitor-induced fibrogenic responses in protocol renal transplant biopsies. J Am Soc Nephrol. 2006;17:881-888. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 58] [Cited by in F6Publishing: 60] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
| 35. | Israni A, Brozena S, Pankewycz O, Grossman R, Bloom R. Conversion to tacrolimus for the treatment of cyclosporine-associated nephrotoxicity in heart transplant recipients. Am J Kidney Dis. 2002;39:E16. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 26] [Article Influence: 1.2] [Reference Citation Analysis (0)] |
| 36. | Kobashigawa JA, Miller LW, Russell SD, Ewald GA, Zucker MJ, Goldberg LR, Eisen HJ, Salm K, Tolzman D, Gao J. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant. 2006;6:1377-1386. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 246] [Cited by in F6Publishing: 256] [Article Influence: 14.2] [Reference Citation Analysis (0)] |
| 37. | Canales M, Youssef P, Spong R, Ishani A, Savik K, Hertz M, Ibrahim HN. Predictors of chronic kidney disease in long-term survivors of lung and heart-lung transplantation. Am J Transplant. 2006;6:2157-2163. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 48] [Cited by in F6Publishing: 46] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
| 38. | O’Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A. Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet. 2002;360:1119-1125. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 198] [Cited by in F6Publishing: 202] [Article Influence: 9.2] [Reference Citation Analysis (0)] |
| 39. | Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation. 1996;62:920-926. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 233] [Cited by in F6Publishing: 242] [Article Influence: 8.6] [Reference Citation Analysis (0)] |
| 40. | Pageaux GP, Rostaing L, Calmus Y, Duvoux C, Vanlemmens C, Hardgwissen J, Bernard PH, Barbotte E, Vercambre L, Bismuth M. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl. 2006;12:1755-1760. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 94] [Cited by in F6Publishing: 92] [Article Influence: 5.1] [Reference Citation Analysis (0)] |
| 41. | Jain A, Vekatramanan R, Eghtesad B, Gadomski M, Mohanka R, Marcos A, Fung J. Long-term outcome of adding mycophenolate mofetil to tacrolimus for nephrotoxicity following liver transplantation. Transplantation. 2005;80:859-864. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 26] [Cited by in F6Publishing: 26] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
| 42. | Créput C, Blandin F, Deroure B, Roche B, Saliba F, Charpentier B, Samuel D, Durrbach A. Long-term effects of calcineurin inhibitor conversion to mycophenolate mofetil on renal function after liver transplantation. Liver Transpl. 2007;13:1004-1010. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 38] [Cited by in F6Publishing: 39] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
| 43. | Romero F, Rodríguez-Iturbe B, Parra G, González L, Herrera-Acosta J, Tapia E. Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int. 1999;55:945-955. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 156] [Cited by in F6Publishing: 162] [Article Influence: 6.5] [Reference Citation Analysis (0)] |
| 44. | Morath C, Schwenger V, Beimler J, Mehrabi A, Schmidt J, Zeier M, Muranyi W. Antifibrotic actions of mycophenolic acid. Clin Transplant. 2006;20 Suppl 17:25-29. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 65] [Cited by in F6Publishing: 70] [Article Influence: 4.1] [Reference Citation Analysis (0)] |