Long-term chronic kidney dysfunction (CKD) after liver transplantation (LT) is still one of the major complications affecting the outcomes of LT recipients. Despite the progress of post-LT management, the cumulative incidence of CKD ≥3 ranges between 36% and 57% and CKD ≥4 from 4.5% to 25%.1
Multiple risk factors have been identified for the development of CKD occurring pretransplant, peritransplant, and posttransplant such as hepatorenal syndrome, diabetes, hemodynamic instability, ischemia-reperfusion syndrome, vena cava clamping, graft dysfunction, calcineurin inhibitors (CNIs), and acute renal failure in the early post-LT.
Over the last few years, the change in donor and recipient characteristics with the use of older and more steatotic grafts as well as LT for sicker recipients (severe obesity, high model for end stage liver disease score, acute on chronic liver failure) might have contributed to further deterioration of posttransplant renal function. Along with other risk factors, including pretransplant kidney changes, diabetes and perioperative events, CNI nephrotoxicity represents a modifiable variable contributing to long-term CKD. Multiple strategies have been studied to reduce the impact of CNIs, in particular, their delayed introduction and minimization. Based on the good results of randomized controlled trials on renal function (the ReSpECT and the DIAMOND studies2,3) with the use of induction therapy with anti–interleukin-2 receptor in combination with corticosteroids, mycophenolate mofetil/mycophenolic acid, and reduced dose or delayed initiation of CNIs, the International Liver Transplant Society recommends the use of induction therapy to optimize renal function.1 However, there is no consensus about type and indication of immunosuppression induction therapy, best timing for CNI introduction, and optimal CNI target levels.
Nair et al4 performed an open-label, multicenter randomized controlled clinical trial to compare the use of antithymocyte globulin (ATG) with delayed CNI initiation (d 10 after LT) and the use of tacrolimus upfront (standard-of-care [SOC] group) introduced within 2 d after LT. The authors randomized 110 patients, 55 in the ATG arm and 55 in the SOC arm. The groups were well matched except for the bodyweight, which was slightly higher in the ATG arm. The primary objective was to evaluate the change in delta creatinine from baseline to 12 mo after LT. Even if there was a statistically significant difference in delta creatinine at 9 mo between the 2 groups, this difference was lost at 12 mo. Moreover, there was no difference in estimated estimated glomerular filtration rate (eGFR) both at 9 and 12 mo post-LT. Mean tacrolimus trough levels were comparable in the 2 arms at different time points during the study. The study also demonstrated the safety of ATG as the rate of biopsy-proven acute rejection was similar in both groups (16.3% versus 12.7%, P = 0.58). Moreover, no differences were observed regarding infection development in the 2 arms.
This study has the merit to address the timely issue of improving long-term renal outcome after LT; nevertheless, some caveats need to be discussed. First, the patients included in the study had normal renal function 82.2 (38.3) mL/min versus 82.9 (32) mL/min, P = 0.92), and possible pre-LT risk factors have not been evaluated. Several studies failed to demonstrate the benefit of a delayed tacrolimus introduction on long-term renal function in patients with good renal function at baseline.5 In contrast, it has been demonstrated that ATG with delayed CNI introduction in patients with pretransplant renal dysfunction was associated with a significant improvement in eGFR at 1 y post-LT compared with patients with SOC treatment.6 This raises the question whether there is an indication to use induction therapy for all LT recipients. It would be interesting to stratify the patients according to their pretransplant and peritransplant risk factors for renal impairment. Indeed, taking into account individual risk of renal outcomes, for example, using a score based on biomarkers such as the PRESERVE score recently published, can help in selecting recipients who can benefit from a renal sparing immunosuppression strategy. The score is based on the combination of 1 clinical variable (hepatitis C virus positivity) and 2 proteins (β-2 microglobulin and CD40) and has a high prediction of eGFR deterioration at 1 y after the transplant (area under the ROC curve 0.81).7
Despite that, in earlier studies, the tacrolimus target levels were higher (8–15 ng/mL); most recent studies have used lower CNI target levels.2,3 This gets to the second point. Considering the benefit associated with the low dose of CNIs, is induction therapy to preserve renal function really necessary? The early introduction of everolimus 1 mo after LT to minimize the dose of tacrolimus aiming lower through levels <5 ng/mL also results in improved renal function.8 This was also recently confirmed in a multicenter French study with a long-term follow-up (36 mo after LT). Among patients with a CKD (eGFR <60 mL/min/1.73 m2) who had an early conversion to everolimus (within 3 mo since LT) or a mid-conversion (between 4 and 12 mo since LT), 55% and 39.4%, respectively, renal function improved to a level of eGFR ≥60 mL/min/1.73 m2.9 Whether this strategy combined with an induction therapy would result in even better outcomes remains to be determined.
The accuracy of the method used for renal function evaluation is important as it has a direct impact on the study results. As acknowledged by the authors, the use of delta creatinine as a measure of renal function lacks sensitivity and specificity compared with GFR. Also, eGFR measured by either modification of diet in renal disease or chronic kidney disease epidemiology collaboration equations is more appropriate; it does not seem to be the most accurate method as measured GFR is more precise but not used in clinical practice. Cystatin C–based GFR equations and new assessment models such as the GRAIL model appear to be superior in evaluating renal function.10
In summary, induction therapy can have a more pronounced benefit in patients with renal impairment at time of transplant. However, it should be combined with other sparing immunosuppressive strategies (ie, delaying CNI introduction, low-trough CNI levels, dual therapy with mycophenolate mofetil/mycophenolic acid or mammalian target of rapamycin inhibitors, mammalian target of rapamycin inhibitor conversion). There is also a need to optimize the monitoring and management of individual risk factors for renal dysfunction through the long posttransplant follow-up (diabetes and arterial hypertension control, avoidance of posttransplant concomitant nephrotoxic drugs and iodinated contrast, and others), ultimately reducing the incidence of long-term CKD after LT.
1. Charlton M, Levitsky J, Aqel B, et al. International Liver Transplantation Society Consensus Statement on immunosuppression in liver transplant recipients. Transplantation. 2018;102:727–743.
2. Neuberger JM, Mamelok RD, Neuhaus P, et al.; ReSpECT Study Group. Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the ‘ReSpECT’ study. Am J Transplant. 2009;9:327–336.
3. TruneČka P, Klempnauer J, Bechstein WO, et al.; DIAMOND† study group. Renal function in de novo liver transplant recipients receiving different prolonged-release tacrolimus regimens—the DIAMOND study. Am J Transplant. 2015;15:1843–1854.
4. Nair A, Hernandez LC, Shah S, et al. Induction therapy with anti-thymocyte globulin and delayed calcineurin inhibitor initiation for renal protection in liver transplantation- a multi-center randomized controlled phase II-B trial. Transplantation. 2022;106:997–1003.
5. Calmus Y, Kamar N, Gugenheim J, et al. Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients. Transplantation. 2010;89:1504–1510.
6. Bajjoka I, Hsaiky L, Brown K, et al. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors. Liver Transpl. 2008;14:66–72.
7. Levitsky J, Asrani SK, Klintmalm G, et al. Discovery and validation of a biomarker model (PRESERVE) predictive of renal outcomes after liver transplantation. Hepatology. 2020;71:1775–1786.
8. Saliba F, De Simone P, Nevens F, et al.; H2304 Study Group. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013;13:1734–1745.
9. Saliba F, Dharancy S, Salamé E, et al. Time to conversion to an everolimus-based regimen: renal outcomes in liver transplant recipients from the EVEROLIVER registry. Liver Transpl. 2020;26:1465–1476.
10. Asrani SK, Jennings LW, Trotter JF, et al. A model for glomerular filtration rate assessment in liver disease (GRAIL) in the presence of renal dysfunction. Hepatology. 2019;69:1219–1230.