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Background The role of interleukin 2 (IL-2) receptor antibodies to avoid the nephrotoxic effects of calcineurin inhibitors in the early post-liver transplant (LT) period is not well defined.
Aim To examine the use of daclizumab induction in LT recipients with renal insufficiency.
Methods Between 2002 and 2005, 62 patients (median pre-LT creatinine 2.4 mg/dL, IQR 1.9–3.7) received daclizumab induction with tacrolimus being administered when serum creatinine was <2.0 mg/dL. A concurrent comparison group (n = 221, 2002–2005) received tacrolimus-based immunosuppression without daclizumab (median pre-LT creatinine 1.1 mg/dL, IQR 0.9–1.4). A second historical comparison group (n = 103, 1995–2005) not receiving daclizumab was matched to the daclizumab patients by pre-LT serum creatinine (2.2 mg/dL, IQR 1.8–3.1). All patients received mycophenolate mofetil and steroids.
Results Serum creatinine improved in the daclizumab group (−1.0 mg/dL, IQR −2.2 to −0.4) and worsened in the concurrent comparison group (+0.2 mg/dL, IQR 0–0.5) from pre-LT to 4 months. However, there was no difference when daclizumab group was compared with the historical comparison group matched on pre-LT creatinine (median change: −0.8 mg/dL vs. −0.7 mg/dL). Daclizumab induction was not associated with improvement in renal function at 4 months (P = 0.34) after adjusting for pre-LT creatinine, age, gender, hepatitis C status and simultaneous liver kidney transplantation.
Conclusion The incremental benefit offered by induction therapy with IL-2 receptor antibodies to preserve renal function is questionable.
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Renal insufficiency, commonly due to calcineurin inhibitor (CNI) nephrotoxicity, is an important source of mortality and morbidity in liver transplant (LT) recipients.1–4 The cumulative incidence of chronic renal failure (estimated glomerular filtration rate ≤29 mL/min/1.73 m2 or development of end stage renal disease) following LT is estimated to be 18% at 5 years, and the risk of end-stage renal disease (haemodialysis or kidney transplantation) at 10% at 10 years.5, 6 Furthermore, patients with chronic renal failure have an elevated risk of death after transplantation (relative risk = 4.55; P < 0.001).7, 8 The problem has recently been compounded by the adoption of the Model for End-Stage Liver Disease (MELD) system for liver allocation in 2002. As this model includes serum creatinine in its scoring system, a growing number of LT recipients have reduced renal function at the time of LT, a major risk factor for post-LT renal insufficiency.9
Given the morbidity and mortality associated with renal insufficiency, various strategies have been attempted to preserve or improve renal function in LT recipients. These include reduction in early exposure to CNI (e.g. delayed introduction or decreased dosage) and/or utilization of non-CNI based induction therapy.4 One such example is the use of daclizumab, an interleukin-2 receptor antagonist, as induction therapy which may provide an immunosuppressive ‘window’ to protect against acute rejection while allowing renal function to improve.10–12
To investigate the effectiveness of daclizumab induction and delayed introduction of CNI on renal function in LT recipients, we analysed our experience at Mayo Clinic Rochester using daclizumab in a renal-sparing protocol. The protocol was implemented between April 2002 and December 2005 with expectation that delaying the introduction of CNI in conjunction with daclizumab-based induction therapy in LT recipients with renal insufficiency would facilitate the recovery of renal function in the early post-LT period without adversely affecting graft or patient survival.
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Table 1 summarizes patient characteristics for the daclizumab group and the comparison groups. The three groups were similar with respect to recipient age, gender, race distribution and donor age, status 1 listing or transplantation for HCV. As expected, serum creatinine concentrations were higher in daclizumab patients than in those in the concurrent group. By design (matching), historical comparison patients had similar serum creatinine as daclizumab patients. This is reflected in the number of SLKTs. The MELD score at LT was higher in the daclizumab patients than in the comparison groups, which is partly attributable to the differences in serum creatinine. Serum bilirubin and INR values were higher in the daclizumab group. The proportion of patients with HCC was 10% in the daclizumab group, 35% in the concurrent comparison group (P < 0.01) and 6% in the historical comparison group (P = 0.4).
Table 1. Baseline patient demographics in the daclizumab group and the two comparison groups
| ||Daclizumab (N = 62)||Concurrent comparison (N = 221)||P value||Historical comparison (N = 103)||P value|
|Recipient age in years, Mean (s.d.)||51 ± 11||53 ± 10||0.27||51 ± 10||0.87|
|Male, N (%)||44 (71)||155 (70)||0.90||62 (60)||0.16|
|Caucasian – 17 missing, N (%)||51 (85)||193 (91)||0.21||77 (87.5)||0.81|
|Donor age in years, Mean (s.d.)||40 ± 18||44 ± 19||0.10||40 ± 18||0.98|
|MELD score at transplant, Mean (s.d.)||28.4 ± 7.7||16.2 ± 8.2||<0.01||25.7 ± 9.6||0.047|
|Transplantation for HCV, N (%)||13 (21)||57 (26)||0.44||15 (15)||0.29|
|Status 1 at transplant, N (%)||2 (3.2)||5 (2.3)||0.65||7 (6.8)||0.49|
|Hepatocellular carcinoma, N (%)||6 (9.7)||76 (34)||<0.01||6 (6)||0.39|
|Simultaneous liver/Kidney transplant, N (%)||16 (26)||5 (2.3)||<0.01||21 (20)||0.73|
|Bilirubin, Median (IQR)||7.8 mg/dL (3.4–22.1)||3.1 mg/dL (1.4–7.7)||<0.01||5.4 mg/dL (2.2–13.6)||0.11|
|INR, Median (IQR)||1.6 (1.3–1.9)||1.4 (1.1–1.7)||<0.01||1.5 (1.2–1.9)||0.14|
|Creatinine, Median (IQR)||2.4 mg/dL (1.9–3.7)||1.1 mg/dL (0.9–1.3)||<0.01||2.2 mg/dL (1.8–3.1)||n/a|
|Creatinine (no SLKT), N, Median (IQR)||N = 46 2.3 mg/dL (1.8–3.5)||N = 216 1.1 mg/dL (0.9–1.3)||<0.01||N = 82 2.1 mg/dL (1.7–2.9)||0.07|
Of the 62 patients who received daclizumab, a majority received at least two doses – 29 (47%) required two doses, and 14 (23%) three. The median time to starting tacrolimus in the daclizumab group was 6 days (range 1–34 days). In 15 patients (24%), tacrolimus was started before the protocol called for, when their creatinine was still greater than 2 mg/dL.
Comparison of renal function outcome between daclizumab and concurrent comparison groups
As has been shown in Table 1, the daclizumab group had a significantly higher serum creatinine at LT than the concurrent comparison group. At 4 months after LT, serum creatinine decreased in the daclizumab group and increased in the concurrent comparison group, which led to a similar serum creatinine concentration: the median creatinine for the former was 1.5 mg/dL and that for the latter 1.4 mg/dL (Table 2). The median change in serum creatinine between pre-LT and 4 months post-LT was −1.0 (−2.2 to −0.4) mg/dL in the daclizumab group and +0.2 (0–0.5) mg/dL in the concurrent comparison group. Similarly, the mean change in eGFR during the same timeframe was a gain of 23 (±27) mL/min 1.73 m2 for the daclizumab group and a loss of 17 (±25) mL/min 1.73 m2 in the concurrent comparison group. This pattern persisted at 1 year for both creatinine and eGFR measurements.
Table 2. Renal function following liver transplantation at 4 months and 1 year in the daclizumab and comparison groups
|Overall group||4 months||1 year|
|Daclizumab (N = 55)||Concurrent comparison (N = 199)||P value*||Historical comparison (N = 77)||P value||Daclizumab (N = 46)||Concurrent comparison (N = 192)||P value*||Historical comparison (N = 73)||P value|
|Creatinine (mg/dL) Median (IQR)||1.5 (1.2–1.9)||1.4 (1.2–1.6)||0.75||1.5 (1.2–1.7)||0.94||1.5 (1.3–1.8)||1.4 (1.2–1.6)||0.93||1.6 (1.3–1.9)||0.42|
|eGFR (mL/min/1.73 m2) Mean (s.d.)||53 ± 22||55 ± 16||0.28||52 ± 22||0.76||51 ± 21||55 ± 15||0.49||47 ± 20||0.44|
|Exclusion of SLKTs||Daclizumab (N = 40)||Concurrent comparison (N = 195)||P value*||Historical comparison (N = 67)||P value||Daclizumab (N = 33)||Concurrent comparison (N = 188)||P value*||Historical comparison (N = 14)||P value|
|Creatinine (mg/dL) Median (IQR)||1.5 (1.2–1.9)||1.4 (1.2–1.6)||0.75||1.5 (1.3–1.8)||0.94||1.6 (1.3–1.9)||1.5 (1.3–1.8)||0.93||1.5 (1.3–1.6)||0.42|
|eGFR (mL/min/1.73 m2) Mean (s.d.)||51 ± 21||55 ± 16||0.28||49 ± 18||0.76||50 ± 24||55 ± 15||0.49||52 ± 18||0.44|
The analysis was repeated while excluding patients who underwent SLKT. As shown in Table 1, the daclizumab group had a significantly higher serum creatinine at LT than the concurrent comparison group. As compared to pre-LT, the serum creatinine decreased (−0.75 mg/dL, IQR −1.6 to −0.2) in the daclizumab group, whereas it increased slightly (+0.2 mg/dL, IQR 0.1–0.5) in the comparison group at 4 months (Table 2).
Pre-LT, 43 (69%) of the daclizumab group and 11 (5%) of the concurrent comparison group had a serum creatinine >2.0 mg/dL. At 4 months, 7 (13%) of the daclizumab group and 8 (4%) of the concurrent comparison group had a serum creatinine >2.0 mg/dL. Figure 1 shows individual data in the daclizumab group (Figure 1a) and in the concurrent comparison group (Figure 1b). Between pre-LT and 4 months post-LT, serum creatinine improved in 80% and worsened in 16% in the daclizumab group. In the concurrent comparison group, improvement was seen in 19% while worsening occurred in 75%. Similarly, eGFR improved in 80% of the daclizumab group and 19% of the concurrent comparison group, whereas the proportion with worsened eGFR was larger in the latter (20% vs. 81%).
Figure 1. Individual level data for change in creatinine from pre-transplant to 4 months after liver transplantation (LT) for daclizumab recipients (a) and concurrent comparison group (b).
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In the following sensitivity analysis, the results of these comparisons did not change. In a per protocol analysis, we further limited our analysis to daclizumab patients who received tacrolimus only when their creatinine was <2 mg/dL and had follow-up data. The results were similar: median change in creatinine was −0.7 (−1.4 to −0.3) mg/dL and mean change in eGFR was +24 (±26) mL/min/1.73 m2.
As expected, the number of persons with at least one episode of renal replacement therapy within 7 days prior to LT was higher in the daclizumab arm, 51% (n = 32) as compared with the concurrent comparison group, 1.8% (n = 4). Nevertheless, most of these episodes were transient haemodialysis. The incidence of renal replacement therapy within the first year post-LT was 6.7% (n = 4) of daclizumab patients vs. 1.4% (n = 3) in the concurrent comparison group (P = 0.02).
Comparison of renal function outcome between daclizumab and historical comparison groups
At 4 months after LT (Table 2), the renal function did not differ between the daclizumab and the historical comparison groups, as gauged by the serum creatinine (1.5 mg/dL in the daclizumab group and 1.5 mg/dL in the comparison group, P = 0.62) or eGFR (53 ± 22 mL/min/1.73 m2 and 52 ± 22 mL/min/1.73 m2 respectively, P = 0.76). The median change in serum creatinine between pre-LT and 4 months post-LT was −0.8 (−1.9 to −0.3) mg/dL in the daclizumab group and −0.7 (−1.5 to −0.1) mg/dL in the historical comparison group. The renal function remained comparable between the two groups in a longer term follow-up with a mean eGFR of 51 ± 21 mL/min/1.73 m2 for the daclizumab group vs. 47 ± 20 mL/min/1.73 m2 for the comparison group (P = 0.44) at 1 year, and 47 ± 15 vs. 46 ± 19 mL/min/1.73 m2 (P = 0.63) at 2 years.
Figure 2 examines the change in serum creatinine from baseline to 4 months as a function of pre-LT renal function. All of the lines slope down, suggesting that the degree of renal recovery is higher in patients with worse renal function at LT. Figure 2a compares the change in renal function between the daclizumab and concurrent comparison groups. Daclizumab patients with worse renal function (right side of the figure) show an improvement in renal function (delta creatinine < 0). In contrast, the concurrent comparison patients with relatively good renal function (left side of the figure) show deterioration in renal function (delta creatinine > 0). More importantly, the figure demonstrates that the trend, as represented by the lines, is essentially identical between the two groups. Figure 2b again shows that the distribution of pre-LT creatinine is the same (by design) between the daclizumab and historical comparison groups. Similar to Figure 2a, the trend lines for the two groups are on top of each other. These two figures suggest that there is no systematic difference between the daclizumab group and the two comparison groups in the pattern of change in renal function from baseline to 4 months after LT. Similar patterns are observed when change in eGFR is examined (data not shown).
Figure 2. Change in renal function from baseline to 4 months as a function of pre-liver transplant renal function in patients receiving daclizumab as compared with concurrent comparison group (a) and historical comparison group (b) matched on pre-transplant creatinine.
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The association of daclizumab induction and change in renal function from pre-LT to 4 months post-LT was examined using the multivariable linear regression analysis. In Table 3, after adjusting for age, gender, SLKT, pre-LT creatinine and HCV diagnosis, daclizumab induction, compared with concurrent comparison group, had a slightly larger increase in creatinine (0.17 mg/dL), which was not significant (P = 0.34). The historical comparison group had an even larger increase in creatinine (0.38 mg/dL), which was statistically significant (P = 0.02) indicating that patients from previous eras of LT had a larger decrease in renal function in the early post-operative period. Consistent with Figure 2, higher pre-LT creatinine was associated with a larger decrease in serum creatinine (−1.87 mg/dL, P < 0.01). Finally, SLKT was associated with a reduction in creatinine of 0.5 mg/dL (P < 0.01) between pre-LT and 4 months post-LT.
Table 3. General linear modelling of predictors of change in renal function from pre-liver transplantation (LT) to 4 months post-LT
|Predictor||Change in creatinine from pre-LT to 4 months|
|Estimate (95% CI)||P value|
|Daclizumab induction||0.17 (−1.17–0.51)||0.34|
|Concurrent comparison group||REFERENCE|| |
|Historical comparison group||0.38 (0.06–0.71)||0.02|
|LN (Creatinine pre-LT)||−1.87 (−2.14 to −1.61)||<0.01|
|Simultaneous liver/Kidney transplant||−0.50 (−0.86 to −0.13)||<0.01|
The incidence of biopsy-proven acute rejection in the daclizumab group was 28% vs. 25% in the historical comparison group (P = 0.95).
Figure 3 summarizes survival outcome in the three groups. Graft failure was observed in 71 subjects including 62 deaths. Both patient (Figure 3a) and graft (Figure 3b) survival was best in the concurrent comparison group, followed by the daclizumab group and lastly by the historical comparison group (P = 0.14 and 0.05 for patient death and graft failure respectively). We conducted Cox proportional hazards analysis to determine the association between daclizumab induction and patient and graft survival. In multivariable analysis (Table 4), after adjusting for recipient age, gender, HCV status, historical comparison group and pre-LT creatinine, daclizumab induction was associated with a nonsignificant 9% reduction in the risk of death (HR = 0.91, 95% CI 0.44–1.89). Additionally, it was associated with a nonsignificant 5% reduction in the risk of graft loss (HR = 0.95, 95% CI 0.47–1.92). Neither adjustment for SLKT nor stratification by HCC status significantly altered the estimates (data not shown).
Table 4. Multivariable Cox proportional hazards analysis of predictors of patient mortality and graft failure (n = 364)
|Predictor||Patient death (62 events)||Graft failure (71 events)|
|Hazard ratio (95% CI)||P value||Hazard ratio (95% CI)||P value|
|Daclizumab induction||0.91 (0.44–1.89)||0.80||0.95 (0.47–1.92)||0.89|
|Historical comparison group||1.52 (0.83–2.78)||0.17||1.77 (0.99–3.18)||0.05|
|LN (Creatinine pre-LT)||1.24 (0.78–1.98)||0.36||1.04 (0.65–1.65)||0.87|
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Induction with IL-2 receptor antibodies is widely accepted in renal transplantation as a part of standard immunosuppression regimen.18 However, its role in LT remains unclear.19 In our cohort of patients with renal insufficiency undergoing LT, daclizumab induction was associated with improvement in renal function compared with the concurrent comparison group patients in whom renal function decreased. However, compared with the historical comparison group matched on pre-LT creatinine, the improvement in renal function in patients treated with daclizumab was similar suggesting that alternative methods for preserving renal function may be equally effective. Given that the use of other IL-2 receptor antibodies such as basiliximab is expected to rise, clarity on whether induction agents offer renal protection is imperative.20
An ideal comparison group would consist of patients from the same time period and with the same renal function as those who received daclizumab. A sufficient number of such patients were not available for this analysis; thus, the concurrent comparison group consisted of patients from the same transplant era regardless of their renal function and the historical comparison group consisted of those with similar renal function, but from a different time period.
Compared with previous reports, this work has several strengths. To our knowledge, our study represents the largest assembled cohort of renal insufficiency patients treated with multiple doses of daclizumab after LT. We were able to compare daclizumab induction with two separate comparison groups and provide clinical context for the use of daclizumab. We also examined the independent effect of daclizumab on improving renal function by multivariable analysis. Furthermore, the convergent validity with the per-protocol sensitivity analysis showed that our results are robust.
It remains unclear whether the difference in the evolution of renal function between the daclizumab and concurrent comparison group is attributable to daclizumab or patient selection. It is likely that some portion of improvement in renal function is driven by the restitution of liver function, leading to improvement in renal perfusion and alleviation of hepatorenal syndrome. Furthermore, it is possible that improvement in renal function associated with daclizumab induction may be due to closer monitoring of patients at the highest risk for progressive renal dysfunction. Adjunctive therapies such as sirolimus may also play a role. Within the first year post-LT, there were 5 (8.1%) persons in the daclizumab group, 2 (1.9%) persons in the historical comparison group, and 12 (5.4%) persons in the concurrent comparison group respectively who received sirolimus. It is possible that persons with renal dysfunction may benefit more from sirolimus given that it is non-nephrotoxic and it may have driven some of the renal improvement seen in the daclizumab group. In addition, the aetiologies of renal dysfunction may vary between the groups leading to the differential effects. However, exclusion of persons undergoing SLKT (and presumably long standing renal dysfunction) did not significantly change the results.
Similar improvement in renal function in the daclizumab group and the historical comparison group matched on pre-LT creatinine suggests that renal protection offered by daclizumab induction, if any, may be equivalent to historical practices to preserve renal function. Furthermore, improvement in renal function may be associated with the mean tacrolimus level or time to initiation of tacrolimus. It is possible that time to initiation of tacrolimus is similar between the historical comparison group and daclizumab group leading to comparable effects on renal function in contrast to the concurrent comparison group. Nevertheless, the use of a historical comparison group spanning the pre-MELD era precludes a stronger conclusion beyond speculation.
There are limited data on daclizumab induction in LT patients with renal insufficiency such as ours. In patients with normal renal function, receipt of daclizumab induction has been associated with a smaller decrease in eGFR at 1 year. In an open-labelled randomized-controlled trial, patients receiving daclizumab induction (2 mg/kg at transplant and 1 mg/kg at 7 days), MMF, corticosteroids and delayed reduced dose tacrolimus (target trough <8 ng/mL) had a decrease in eGFR of 13.63 mL/min as compared with a 21.22 mL/min decrease in a reduced dose tacrolimus arm and 23.61 mL/min decrease in a standard dose tacrolimus arm (trough level >10 ng/mL).21
To date, there are no prospective, randomized-controlled trials investigating the role of IL-2 receptor antibodies specifically in patients with renal insufficiency. In a retrospective study, Emre et al. examined patients with creatinine >3 mg/dL undergoing LT between 1994 and 1999 and treated with either single dose daclizumab induction (n = 25) or low-dose tacrolimus (n = 48) in addition to MMF and steroids. In the daclizumab group, tacrolimus (0.1 mg/kg) was added when creatinine improved by 25%. There was no difference in creatinine levels at 3 months or 1 year after LT, although the time to creatinine improvement by 25% was faster in the daclizumab group (3.6 days vs. 12.2 days).22 In our study, patients receiving daclizumab may have also had an earlier improvement in renal function; however, at 4 months, similar changes in renal function were observed in the daclizumab and historical comparison groups. In addition, despite the daclizumab group having sicker patients as compared with the historical comparison group (MELD 28 vs. 25, P = 0.047) and a significant number (25%) receiving tacrolimus despite a creatinine >2 mg/dL, serum creatinine did improve. These potential benefits of daclizumab, however, can only be answered with randomized-controlled trials.
Basiliximab, a chimeric IL-2 receptor antibody is used in patients after LT. However, less than robust data exist to define its role in patients with renal insufficiency. An open label nonrandomized trial showed a lower incidence of renal insufficiency at 3 months in patients receiving basiliximab induction vs. low-dose tacrolimus. However, patients with normal renal function were included and by 6 months, renal function was similar and incrementally worse in both arms.23 Given that the mechanism of action is the same for both daclizumab and basiliximab, the results of our study have important implications for the use of all IL-2 receptor antibodies in renal sparing protocols.12 In our opinion, a randomized trial is needed to examine the use of IL-2 receptor antibodies to minimize exposure to CNI in the early post-LT period in patients with renal insufficiency.
By and large, induction therapy has not been shown to improve survival in LT recipients. Yoshida et al. reported similar survival in patients receiving daclizumab induction vs. standard-dose tacrolimus and MMF at 1 year (86.6% vs. 92.9%).24 A recently completed randomized multicentre trial reported that HCV positive patients with normal renal function who received daclizumab had a similar patient (87% vs. 81%) and graft survival (84% vs. 78%) at 2 years as compared with patients who did not receive induction.25
Similarly, our data are not sufficient to determine whether daclizumab was associated with a survival benefit in liver recipients with renal insufficiency. Part of the difficulty arises from separating the incremental benefit of daclizumab, if any, from the higher mortality associated with patients who have renal dysfunction. Similarly, whether any of the difference in graft survival between the daclizumab and historical comparison group is attributable to daclizumab vs. improvement in LT outcome over time is not clear. After exclusion of persons with SLKT and only comparing the daclizumab group and the historical comparison group, the survival at 1, 3 and 5 years is 82.6%, 80.4% and 78.1% vs. 84.1%, 74.3% and 69.0% respectively. However, such a comparison does not take into account a change in practice over time. In the multivariable analysis, adjustment for the historical reference group and in light of current practices (compare to concurrent comparison group) adjusting for SLKT did not significantly change the results.
In summary, daclizumab induction resulted in recovery of renal function such that it became comparable with a group of contemporaneous patients treated with standard immunosuppression without adversely affecting patient and graft survival. However, as highlighted by a similar improvement in renal function in a matched historical comparison group, whether the improvement in renal function can be attributed to use of daclizumab per se remains unclear. Our study highlights that despite the continued use if IL-2 receptor antibodies in LT recipients, data on its renal sparing benefits remain limited. The incremental benefit offered by IL-2 receptor antibodies as compared with other strategies to preserve renal function needs to be compared in a randomized-controlled trial.