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Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): The TRY study
Article first published online: 28 AUG 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 15, Issue 9, pages 1083–1091, September 2009
How to Cite
Karie-Guigues, S., Janus, N., Saliba, F., Dumortier, J., Duvoux, C., Calmus, Y., Lorho, R., Deray, G., Launay-Vacher, V. and Pageaux, G.-P. (2009), Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): The TRY study. Liver Transpl, 15: 1083–1091. doi: 10.1002/lt.21803
- Issue published online: 28 AUG 2009
- Article first published online: 28 AUG 2009
- Manuscript Accepted: 17 MAR 2009
- Manuscript Received: 22 DEC 2008
The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m2 in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (−16% versus −30% and −15% versus −33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m2, respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone agroup, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term. Liver Transpl 15:1083–1091, 2009. © 2009 AASLD.
Renal impairment is a frequent complication after liver transplantation (LTx) and is usually enhanced or caused by the use of a calcineurin inhibitor (CNI)–based immunosuppressive regimen. Renal impairment has been often associated with an increased risk of morbidity and mortality after transplantation. Kidney damage is defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), as evidenced by abnormalities in the composition of the blood or urine or abnormalities in imaging tests. The Kidney Disease: Outcomes Quality Initiative/Kidney Disease: Improving Global Outcomes (K/DOQI-KDIGO) classification of chronic kidney disease (CKD) stratifies renal alterations into 5 stages. Stages 1 and 2 include patients with evidence of kidney damage and a GFR greater than or equal to 90 mL/minute/1.73 m2 (stage 1) or within 90 to 60 mL/minute/1.73 m2 (stage 2). Stages 3 to 5 are defined by a reduction in GFR: between 60 and 30 mL/minute/1.73 m2 (stage 3), between 30 and 15 mL/minute/1.73 m2 (stage 4), or below 15 mL/minute/1.73 m2 (stage 5).1, 2
In routine clinical practice, the GFR is difficult to measure. Gold-standard methods precisely measuring the GFR, such as inulin or validated-isotope clearances, are costly and time-consuming. Several creatinine-based formulae such as the Cockcroft-Gault (CG) formula3 and those derived from the Modification of Diet in Renal Disease (MDRD) study4 have been developed to estimate the GFR in patients with CKD. The abbreviated MDRD (aMDRD) equation, excluding urea and albumin, is as accurate as the original 6-variable formula.5 These equations have been evaluated in a large cohort of LTx recipients (n = 1447), and the MDRD equations (6, 5, and 4 variables) have been identified as being more precise than the CG formula.6
CKD is a common complication after LTx. Ojo et al.7 reported a cumulative incidence of CKD [defined as GFR ≤ 29 mL/minute/1.73 m2 (calculated with the aMDRD formula)] in 36,849 LTx recipients of 8.0% at 1 year and 18.1% at 5 years; this was higher than that found in heart, lung, or heart-lung transplant recipients. O'Riordan et al.8 assessed with the aMDRD formula the 10-year cumulative incidence of CKD among 230 liver recipients using the K/DOQI-KDIGO classification. The 10-year cumulative incidence for each stage of CKD was as follows: 9.6% of patients had normal kidney function (GFR > 90 mL/minute/1.73 m2) with or without kidney damage (stage 0/1), 53.7% of patients had mild renal insufficiency (GFR = 60–89 mL/minute/1.73 m2 and kidney damage; stage 2), 56.8% of patients had moderate renal insufficiency (GFR = 30–59 mL/minute/1.73 m2; stage 3), 6.1% of patients had severe renal insufficiency (GFR = 15–29 mL/minute/1.73 m2; stage 4), and 2.6% of patients had kidney failure (GFR <15 mL/minute/1.73 m2; stage 5).
Several authors have reported on the impact of renal alterations on morbidity and mortality after LTx. In their study, Ojo et al.7 found that nonrenal solid organ transplant recipients with CKD had a mortality risk of 4.55 in comparison with transplant recipients who did not have CKD. Moreno et al.9 reported that the survival at 67 months was significantly lower (63%) among LTx patients with CKD versus those without this complication (71%).
Despite numerous publications, little is known regarding the prevalence of CKD in LTx. It varies widely, ranging from 4%10 to 79%11 with follow-up of 1 to 13 years. The definition of CKD in these studies varies. Some existing reports10, 12 rely on serum creatinine (SCr), which is not appropriate for evaluating renal function if not interpreted together with the sex, age, and weight of the patient, and others use a GFR but with different methods of estimation and with nonstandard cutoff values for CKD. For instance, Cohen et al.13 reported that the prevalence of a GFR < 40 mL/minute/1.73 m2 (as determined by iothalamate clearance) is 27.5% at 5 years, whereas Sheiner et al.11 showed that the prevalence of a GFR < 43 mL/minute/1.73 m2 at the same time point after LTx is 79.5%. In the latter study, the renal function was estimated with the CG formula and standardized later to a body surface area of 1.73 m2.11
The primary objective of this study was to report on the prevalence of renal insufficiency in LTx patients before and at 1, 12, and 60 months after LTx according to the K/DOQI-KDIGO classification. A coprimary endpoint was to compare the modifications in patient's renal function according to the immunosuppressive regimen at 1, 12, and 60 months after LTx.
PATIENTS AND METHODS
TRY is a national, multicenter, observational study.
We identified a retrospective cohort of 1508 patients 18 years old or older at the time of LTx who underwent primary, single-organ LTx before March 2002 in 1 of 15 French centers (of a total of 21 LTx centers in France) participating in the study. This cutoff was chosen to ensure that the follow-up information (60 months) would be complete. Patients in whom renal replacement therapy (dialysis or kidney transplantation) preceded LTx and patients undergoing dialysis within 1 month after LTx were not included in the study. Only patients alive at the time of data collection (between July 2007 and February 2008) were included. The rationale for excluding the patients who died was that these patients frequently developed acute renal dysfunction during the terminal stage of their illness, regardless of their previous renal function. Thus, inclusion of these patients may have given rise to misleading results. In short, the inclusion criteria in our study selected patients with good renal prognosis.
The following data were recorded from the medical files of the patients at 4 time points (before LTx and 1, 12, and 60 months after LTx): baseline demographic (gender and age) and clinical (weight, height, indication for LTx, and hemoglobin) characteristics and laboratory data on hepatic (total serum bilirubin, serum albumin, prothrombin time, alanine aminotransferase, and aspartate aminotransferase) and renal (SCr and blood urea nitrogen) functions. Also documented were the presence of hypertension (mention of a diagnosis in the medical file or a need for antihypertensive medications), diabetes mellitus (mention of a diagnosis in the medical file or a need for oral hypoglycemic agents or insulin), hepatitis C virus (HCV) infection (before transplantation and recurrence), and anemia (World Health Organization definition: hemoglobin level < 12.0 g/dL for women and < 13.0 g/dL for men14). The immunosuppression regimen was recorded, as were the doses and the trough serum CNI levels (for cyclosporine, a C0 sample but not a C2 sample). Patients were treated according to the usual immunosuppressive regimen of each center. For all centers participating in the study, data were collected by only 1 person in order to provide data collection uniformity.
To reach the primary objective of the TRY study (a report on the prevalence of renal insufficiency in LTx patients before and at 1, 12, and 60 months after LTx according to the K/DOQI-KDIGO classification), all 1508 patients included in the study were analyzed. To reach a coprimary endpoint (a comparison of the modifications in a patient's renal function according to the immunosuppressive regimens), the patients were analyzed according to their immunosuppressive regimens at the time of transplant (1 month after LTx) and at 12 and 60 months post-LTx. The patients had to have the same immunosuppressant protocol at each time point: a CNI alone with or without corticosteroids (CNI-alone group, n = 624) or a CNI in combination with mycophenolate mofetil (MMF) with or without corticosteroids (MMF group, n = 117). Thus, the CNI-alone group comprised only those patients who started on a CNI alone at the time of transplant and who remained on this regimen at 12 and 60 months post-LTx, and the MMF group comprised only those patients who started on a CNI in combination with MMF at the time of transplant and who remained on this regimen at 12 and 60 months post-LTx. Renal function was compared for the 2 treatment groups. The renal function of patients who received other non-CNI, non-MMF immunosuppression (azathioprine, sirolimus, and everolimus) or who changed their immunosuppressant protocol during the follow-up (n = 767) were not compared to the CNI-alone group and MMF group because of the multiplicity of immunosuppressive combinations.
The estimated GFR was calculated according to the aMDRD formula15:
Normal renal function was defined as a GFR > 90 mL/minute/1.73 m2. The Mayo Model for End-Stage Liver Disease (MELD) score was calculated with the following equation16:
where INR is the international normalized ratio. Because patients included in the study were transplanted before the introduction of the MELD score, centers participating in the study used the prothrombin time but not INR as a marker of coagulation in these patients. We estimated INR from the prothrombin time according to the following formula to calculate the MELD score17:
Univariate analysis was used to compare the 2 groups of patients. For these analyses, the Mann-Whitney and Student t tests were used to compare continuous data. The chi-square and Fischer exact tests were performed to compare categorical variable.
Multivariate analysis (multiple linear regressions) was performed, focusing on the use or nonuse of MMF for immunosuppressive therapy at each time point after transplantation. Other variables entered into the analysis included gender, age, body mass index (BMI) at 1 month post-transplantation, MELD score, alcoholic and hepatitis C cirrhosis (pretransplant liver disease), preoperative renal insufficiency (GFR < 60 mL/minute/1.73 m2), diabetes mellitus or systemic hypertension before transplantation and de novo, hepatitis C recurrence, year of transplant (before or after 1997), and acute kidney injury at 1 month after LTx (defined as a 50% or greater increase in SCr at 1 month post-LTx versus pretransplant values). The cutoff of 1997 (MMF market availability in France) for the year of transplant was chosen to take into account an era when fewer immunosuppressive agents were available and when the tendency was to use higher doses of CNIs. Complete model covariate data for the 2 groups of patients were available for 87.4% of the patients. Missing data were imputed to the BMI and MELD score. A P value lower than 0.05 was considered significant. All the analyses were performed with SAS statistical software, version 8.02 (SAS, Inc., Cary, NC).
From July 2007 to February 2008, a total of 1508 patients, 18 to 72 years old (mean age = 48.2 ± 10.6), were included in the study. The population was predominantly male (64.5%). The most common indications for LTx were alcohol-related cirrhosis (31.2%), hepatitis C–related cirrhosis (20.6%), and cholestatic liver diseases (9.8%). The mean follow-up time post-LTx was 9.2 ± 3.4 years (5.0–21.0 years). Approximately one-third (31.2%) of the patients were transplanted between 1986 and 1996, and the remaining were transplanted between 1997 and 2002. Table 1 shows the baseline characteristics of the study cohort before transplantation stratified into the 2 treatment groups. Patients in the MMF group, as opposed to patients in the CNI-alone group, had a lower baseline GFR (87.6 versus 97.3 mL/minute/1.73 m2, P = 0.003) and were more likely to have hypertension (18.8% versus 12.8%, P = 0.05). In addition, in the MMF group versus the CNI-alone group, there was a significantly higher percentage of patients with alcohol-related cirrhosis (38.5 versus 28.0, P = 0.02), and there was a significantly lower percentage of patients with hepatitis C–related cirrhosis (10.3 versus 25.3, P = 0.0004). Subjects were otherwise similar between the 2 groups.
|Whole Population (n = 1508)||CNI-Alone Group (n = 624)||MMF Group (n = 117)||P*|
|Age (years)||48.2 ± 10.6||48.6 ± 10.7||48.3 ± 11.3||NS|
|Male sex [no. (%)]||972 (65)||404 (64.7)||71 (60.7)||NS|
|Primary liver disease [no. (%)]|
|Alcoholic cirrhosis||470 (31.2)||175 (28.0)||45 (38.5)||0.02|
|Hepatitis C cirrhosis||310 (20.6)||158 (25.3)||12 (10.3)||0.0004|
|Cholestatic liver diseases||147 (9.8)||48 (7.7)||14 (12.0)||NS|
|Total bilirubin (mg/L)||74.8 ± 100.6||69.0 ± 96.8||64.6 ± 96.2||NS|
|Serum albumin (g/L)||31.8 ± 6.9||32.0 ± 7.0||31.8 ± 6.6||NS|
|Prothrombin time (%)||54.3 ± 21.3||54.9 ± 20.5||52.7 ± 23.4||NS|
|MELD score†||15.0 ± 6.9||13.9 ± 7.2||14.7 ± 8.9||NS|
|≥17 [no. (%)]||402 (32.0)||162 (28.4)||34 (30.9)||NS|
|Hypertension [no. (%)]||159 (10.5)||76 (12.8)||22 (18.8)||0.05|
|Diabetes [no. (%)]||189 (12.5)||65 (10.5)||12 (10.3)||NS|
|Serum creatinine (μmol/L)||81.9 ± 34.1||76.1 ± 25.4||93.3 ± 62.9||0.001|
|Blood urea nitrogen (mmol/L)||5.8 ± 4.4||5.3 ± 3.1||6.1 ± 4.3||NS|
|GFR (mL/minute/1.73 m2)||94.7 ± 31.9||97.3 ± 32.7||87.6 ± 37.7||0.003|
|<90 mL/minute/1.73 m2||689 (45.7)||263 (42.2)||64 (54.7)||0.01|
|<60 mL/minute/1.73 m2||163 (10.8)||51 (8.2)||23 (19.7)||0.0001|
At 1 month post-transplantation, all but 124 (8.2%) patients were receiving steroids. Continuation of steroids was reported for 66.4% and 22.8% of patients at 12 and 60 months, respectively. The main CNI used at 1, 12, and 60 months was tacrolimus in 53.7%, 57.3%, and 59.5% of patients, respectively, and 46.4%, 42.4%, and 38.9% were treated with cyclosporine. Triple therapy with either MMF or azathioprine in combination with steroids and a CNI was used in 43.3%, 20.8%, and 7.0% of the patients at 1, 12, and 60 months post-transplantation, respectively. Dual therapy comprising either a CNI and steroids or a CNI and an antimetabolite was used in 49.8%, 54.4%, and 35.1% of the patients at 1, 12, and 60 months post-transplantation, respectively. The remaining patients were treated with monotherapy: 6.9%, 24.7%, and 57.8% of the patients at the same time points post-transplantation. On the whole, 30.8%, 15.3%, and 5.6% of patients were treated with azathioprine and 13.8%, 14.3%, and 21.5% of patients were treated with MMF at 1, 12, and 60 months, respectively.
There were no significant differences between the 2 treatment groups for both CNI doses and blood levels at 12 and 60 months post-transplantation, whereas at 1 month, there was a significant difference between the CNI doses and tacrolimus blood levels (Table 2).
|CNI-Alone Group (n = 624)||MMF Group (n = 117)||P|
|Level (ng/mL)||11.9||9.5||< 0.0001|
Hypertension and Diabetes Mellitus
Hypertension was preexisting in 10.5%; another 25.8%, 43.4%, and 55.1% developed new-onset hypertension at 1, 12, and 60 months post-transplantation, respectively. Diabetes was reported in 12.5% of the patients before LTx and in 15.9%, 19.2%, and 22.5% at 1, 12, and 60 months after LTx, respectively.
Baseline Renal Function
The mean baseline GFR for the whole cohort (n = 1508) was 94.7 mL/minute/1.73 m2. The mean baseline GFR in patients of the MMF group was significantly lower than the baseline GFR in patients of the CNI-alone group: 87.6 versus 97.3 mL/minute/1.73 m2 (P = 0.003). A GFR < 60 mL/minute/1.73 m2 was observed in 10.8% (n = 163) of the patients in the whole population and in 19.7% and 8.2% of the patients in the MMF group and CNI-alone group, respectively. The baseline renal function in the MMF group was thus worse than that in the CNI-alone group.
Posttransplantation Renal Function in the Whole Study Population
The GFR after LTx decreased in all but 255 (16.9%) patients. The mean GFR at 1, 12, and 60 months post-transplantation for the whole cohort was 65.7, 61.7, and 58.4 mL/minute/1.73 m2, respectively; this represented a 30.6% to 38.3% decrease from the baseline (94.7 mL/minute/1.73 m2). Ten patients (0.7%) required renal replacement therapy within 60 months. The prevalence of a GFR < 60 mL/minute/1.73 m2 after transplantation was approximately 5 times that observed before transplantation: 47.7%, 51.2%, and 57.7% of the patients at 1, 12, and 60 months, respectively. The renal function of the patients by the stage of CKD is shown in Table 3.
|Stage of Kidney Disease||GFR (mL/minute/1.73 m2)||Before LTx [% (n)]||After LTx [% (n)]|
|1 Month||12 Months||60 Months|
|1||≥90||54.3 (819)||15.9 (240)||7.7 (117)||5.7 (86)|
|2||60–89||34.9 (526)||36.4 (549)||41.1 (619)||36.6 (552)|
|3||30–59||9.5 (143)||43.9 (662)||48.7 (734)||52.7 (795)|
|4||15–29||1.1 (17)||3.5 (53)||2.4 (36)||3.7 (56)|
|5||<15 and HD||0.2 (3)||0.3 (4)||0.13 (2)||1.3 (19)|
Posttransplantation Renal Function According to the Immunosuppressive Protocol
The decrease in GFR at 12 and 60 months post-transplantation was significantly lower in the MMF group compared to the CNI-alone group: −15.5% versus −29.9% (P = 0.04) and −14.6% versus −33.3% (P = 0.01), respectively. The GFR decrease at 1 month was not significantly different between the 2 groups: −16.6% in the MMF group versus −27.0% in the CNI-alone group, respectively (P = 0.1; Fig. 1). After adjustments for gender, age, MELD score, BMI at 1 month after LTx, alcoholic and hepatitis C cirrhosis (pretransplant liver disease), preoperative GFR < 60 mL/minute/1.73 m2, hypertension and diabetes (pre-transplant and/or de novo), hepatitis C recurrence, transplant year, and presence or absence of acute renal injury at 1 month post-transplantation, the use of MMF remained an independent factor for a lower decrease in the GFR at each time point after transplantation. A higher MELD score, a preoperative GFR < 60 mL/minute/1.73 m2, and renal dysfunction at 1 month post-transplantation were significant predictors for a higher decrease in the GFR at all time points after transplantation, whereas increasing age was a significant predictor of a decreased GFR at 12 and 60 months but not at 1 month (Table 4).
|Variable||Coefficient and P Value|
|1 Month||12 Months||60 Months|
|Age at the time of transplantation||−0.11||NS||−0.38||0.0030||−0.38||0.0068|
|BMI at 1 month||−0.34||NS||−0.32||NS||−0.41||NS|
|Alcoholic cirrhosis (pre-transplant)||−3.24||NS||−5.11||NS||−6.00||NS|
|Hepatitis C cirrhosis (pre-transplant)||−4.15||NS||1.84||NS||2.17||NS|
|Hypertension (pre-transplant or de novo)||−1.49||NS||0.09||NS||0.13||NS|
|Diabetes (pre-transplant or de novo)||−2.32||NS||−4.59||NS||−5.87||NS|
|Hepatitis C recurrence||−3.38||NS||2.20||NS||−1.21||NS|
|GFR < 60 mL/minute/1.73 m2 (pre- transplant)||−37.81||<0.0001||−41.77||<0.0001||−44.21||<0.0001|
|Acute kidney injury at 1 month (≥50% increase from baseline in SCr)||−39.33||<0.0001||−19.01||0.0024||−16.21||0.0156|
|Transplantation before 1997||7.74||NS||−0.32||NS||−4.44||NS|
|Use of azathioprine||−2.35||NS||−0.54||NS||4.15||NS|
|Use of MMF||7.88||0.0408||10.91||0.0036||12.56||0.0022|
This study demonstrates that CKD is a frequent complication after LTx, even in a selected population including living patients who did not have dialysis during the first month post-transplantation. There was a progressive worsening of renal function after LTx: patients lost 30% to 38% of their GFR between 1 and 60 months post-transplantation. At 60 months, 57.7% of the patients had a GFR < 60 mL/minute/1.73 m2. O'Riordan et al.8 reported that 71.1% of patients surviving to 5 years post-transplantation had a GFR < 60 mL/minute/1.73 m2 (estimated with the MDRD formula). One possible explanation for this difference could be the fact that the inclusion criteria in our study selected patients with good renal prognosis. Despite that, only 15.9%, 7.8%, and 5.7% of patients had a normal GFR > 90 mL/minute/1.73 m2 at 1, 12, and 60 months after LTx.
Acute renal failure (ARF) is also a well-recognized complication after LTx. Cabezuelo et al.18 classified posttransplantation ARF into that occurring early (first week) or late (second through fourth week). In our study, we chose to start the data collection on renal function at 1 month after transplantation in order to avoid ARF, which was not the aim of the TRY study.
Patients presenting for LTx, often cirrhotic (n = 1189 in the TRY study), have several underlying conditions (decreased SCr production secondary to decreased hepatic creatine synthesis19 and decreased skeletal muscle mass20) that contribute to falsely low SCr concentrations and often cause creatinine-based methods to overestimate the true GFR. In a study of 18 patients with cirrhosis and with a reduced 125I-iothalamate GFR (mean = 58 ± 5 mL/minute/1.73 m2), Skluzacek et al.21 reported that the GFR by the MDRD equation was 18.7 mL/minute/1.73 m2 (32%) greater than the measured GFR (P = 0.0004), and the GFR by the CG formula was the least accurate (+30.1 mL/minute/1.73 m2 or 52%, P = 0.0001) versus renal iothalamate. Another study conducted in 56 patients with cirrhosis also showed that the GFR was overestimated by calculation (CG formula). It provided accurate estimates in patients with normal inulin GFR (mean = 113 mL/minute/1.73 m2). However, in patients with decreased GFR (mean = 56 mL/minute), the estimated GFR overestimated inulin clearance by 40%.22
In contrast to these 2 studies, Gonwa et al.23 found that the CG and MDRD (4-, 5-, and 6-variable) equations underestimated the real pretransplant GFR in 1447 patients with a mean measured 125I-iothalamate GFR of 91 mL/minute/1.73 m2. However, when these patients were divided into 2 groups (those with a measured GFR < 40 mL/minute/1.73 m2 and those with a measured GFR > 40 mL/minute/1.73 m2), the equations consistently overestimated the GFR in the setting of decreased renal function.24 For example, in this group, the mean measured GFR was 22.6 ± 11.1 mL/minute/1.73 m2, whereas the GFR estimated with the aMDRD formula was 44.5 ± 28.8 mL/minute/1.73 m2.6 In the whole study population at the time of the initial evaluation, the MDRD equations were associated with a greatest precision than the CG formula. In the same study, the authors reported that at 1 and 5 years post-transplant, the MDRD equations showed better precision and accuracy. This may be explained by the fact that at 1 and 5 years post-transplant, patients are generally stable, and this population resembles patients with CKD, for whom the MDRD formulae were validated. In our study, only 2.4% of patients had a pre-LTx GFR < 40 mL/minute/1.73 m2. This would not impair our interpretation of the evaluation of the GFR. Therefore, we used the aMDRD equation to calculate the GFR in the TRY study.
Both cyclosporine and tacrolimus are CNIs, and 1 of their commonly observed side effects after long-term use is renal dysfunction.25 Although CNI-induced renal dysfunction initially is reversible, there is a risk of structural damage such as glomerular sclerosis or tubular atrophy that can lead to chronic alterations in glomerular filtration.25 As a result, CNI therapy is 1 of the major causes of post-LTx renal dysfunction.24, 26 In this work, we observed that at 12 and 60 months, LTx recipients treated with a CNI in combination with MMF had better kidney function than those on a CNI alone. Interestingly, this difference in GFR modifications could not be explained by CNI exposure reduction at these time points because cyclosporine and tacrolimus mean dosages and blood levels did not differ at 12 and 60 months post-transplantation between the 2 groups (Table 2). However, there was a significant difference between the CNI doses and tacrolimus levels at 1 month after LTx. There are studies indicating that early exposure to CNIs is 1 of the determinants of long-term renal function,10, 27 and this has been confirmed by the findings of our study. It seems likely that it is important to avoid a significant reduction in renal function in the first month after transplant by limitation of the exposure to CNIs in both patients with preexisting renal dysfunction and those with normal renal function.
MMF does not interfere with the actions of calcineurin and does not cause renal toxicity.28 Positive effects of the introduction of MMF as a rescue treatment for renal dysfunction due to CNI toxicity have been reported in several studies.28–30 Moreover, MMF could have nephroprotective properties. Romero et al.31 noted that MMF prevented progressive renal failure in rats who underwent 5/6 renal ablation and hypothesized that MMF has an antiproliferative effect. In fact, in various cells lines (ie, smooth muscle cells, renal tubular cells, and mesangial cells), MMF reduced or even abrogated proliferation in response to proliferative stimuli.32 These effects on endothelial cells may counteract the harmful vascular effects of CNIs 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 reduced decrease in the GFR observed in TRY patients receiving MMF may not be due only to CNI dose reduction at 1 month after LTx.
Some limitations of the study have to be considered. Because of the retrospective character of the study, it is not possible to provide information about what determined the use of MMF or CNIs and why MMF was chosen in the first month post-LTx. Furthermore, there was an unequal distribution of patients in the 2 treatment groups (624 versus 117). The small number of patients in the MMF group could be partially explained by the fact that approximately one-third (31.2%) of the patients were transplanted before MMF market availability in France (1997). As patients were not matched, there were 2 main differences between the 2 groups of treatment that might influence the findings of this study: more patients without HCV got MMF, and the initial GFR was significantly lower in patients receiving MMF. Asfandiyar et al.33 reported that HCV infection is a risk factor for renal dysfunction after LTx with a relative risk of 2.58 (P = 0.045), even if the negative impact of HCV positivity on renal function has not been confirmed in the long term.34 With respect to the lower initial GFR in patients of the MMF group compared to those of the CNI-alone group, on the one hand, it could be considered a cause of an initial selection bias, but on the other hand, these patients were significantly more at renal risk after LTx because of their lower initial GFR. Furthermore, a multivariate analysis confirmed a relationship between the immunosuppressive protocol and the decrease in the GFR at each time point with a positive impact for the group with MMF.
Older age,7, 9, 10 a higher MELD score,35 preoperative renal insufficiency,7 early postoperative kidney dysfunction,7 and cyclosporine treatment7 as variables associated with postoperative renal dysfunction were identified in previous studies; this was similar to our results. In our cohort, neither hypertension nor diabetes (pre-transplant or de novo for both) was significantly associated with a GFR decrease at any time points after LTx. These results are in line with those previously reported by Ojo et al.7 for hypertension and by O'Riordan et al.8 for diabetes.
We conclude from this large cohort study that the prevalence of CKD among LTx recipients during the early and late postoperative periods is high: 48%, 51%, and 58% of the patients have a GFR < 60 mL/minute/1.73 m2 at 1, 12, and 60 months post-transplantation, respectively. The reduction in the GFR is less marked in patients who started on a CNI in combination with MMF at the time of transplant, and this could be related to less important CNI exposure early after LTx. (It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.) Increasing age, the MELD score, and a preoperative GFR < 60 mL/minute/1.73 m2 are significant predictors of a decrease in GFR. The presence of these factors may thus identify a subgroup at risk for whom immunosuppression treatment with nonnephrotoxic drugs as early as possible is appropriate.
Under the direction of the TRY Scientific Committee, the TRY study has been coordinated by Information Counseil Adaptation Rènale, a National Medical Advisory Service on the interactions between drugs and the kidney (ie, drug dosage adjustment, drug nephrotoxicity, and drug-drug interactions with immunosuppressive therapies), which is located in the Department of Nephrology at Pitie-Salpetriere Hospital (Paris, France). The members of the TRY Scientific Committee are (in alphabetical order) Y. Calmus (Paris, France), G. Deray (Paris, France), J. Dumortier (Lyon, France), C. Duvoux (Créteil, France), S. Karie-Guigues (Paris, France), V. Launay-Vacher (Paris, France), R. Lorho (Rennes, France), G. P. Pageaux (Montpellier, France), and F. Saliba (Villejuif, France). The members of the TRY Study Group are (in alphabetical order) M. Altieri (Caen, France), H. Audin-Mamlouk (Montpellier, France), M. Bismuth (Montpellier, France), K. Boudjema (Rennes, France), Y. Calmus (Paris, France), P. Campan (Marseille, France), N. Carbonell (Paris, France), D. Castaing (Villejuif, France), P. Compagnon (Rennes, France), F. Conti (Paris, France), C. Cros (Paris, France), N. Declerck (Lille, France), S. Dharancy (Lille, France), C. Ducerf (Lyon, France), J. Dumortier (Lyon, France), F. Durand (Clichy, France), C. Duvoux (Créteil, France), V. Esnault (Clichy, France), M. Hurtova (Créteil, France), M. Huynh (Paris, France), A. Laurent (Créteil, France), V. Leroy (Grenoble, France), R. Lorho (Rennes, France), R. Maar (Lyon, France), F. Navarro (Montpellier, France), I. Ogier (Villejuif, France), I. Ollivier (Caen, France), G. P. Pageaux (Montpellier, France), A. Plages (Caen, France), G. Rousseau (Paris, France), A. S. Salabert (Paris, France), J. Salandre (Lyon, France), F. Saliba (Villejuif, France), D. Samuel (Villejuif, France), O. Scatton (Paris, France), and P. Wolf (Strasbourg, France).
- 1National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1–S266.
- 14Nutritional Anemias: Reports of a WHO Scientific Group. Geneva, Switzerland: World Health Organization; 1968.
- 15A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000; 11: 0828., , .