Immunosuppression in liver transplant recipients with renal impairment
Authors: C. Duvoux, G.P. Pageaux
Journal: Journal of Hepatology (2010)

IntroductionRenal injury has been recognized as an increasingly prevalent complication of liver transplantation (LT) over the last decade. Both acute and chronic renal injuries occur with high frequency in liver transplant recipients and are associated with increased morbidity and mortality. The risk of immediate post-LT kidney dysfunction is increased in patients with pre-transplant kidney failure, hepato-renal syndrome (HRS), and intra-operative or post-operative hypotension. Thus with the improvement in life expectancy after LT, chronic kidney disease (CKD) has emerged as an increasingly prevalent complication among long-term survivors. Although post-LT renal injury is often multifactorial, one of the dominant mediators is the use of calcineurin inhibitors (CNI), namely Cyclosporine (CsA) and Tacrolimus (Tac), which are the cornerstone of immunosuppression in LT recipients. These drugs indeed intrinsically share a variety of renal toxicities, ranging from oligoanuric acute renal failure to chronic kidney disease.Optimization of immunosuppression for protection of kidney function must, therefore, be considered a major goal after LT, in particular for patients with already impaired renal function.The aim of this article is to review the epidemiology, risk factors, and consequences of post-LT renal dysfunction and to discuss the current approaches to overcome CNI toxicity after LT, both in the early post-operative period and in the long-term, focusing on manipulation of immunosuppressive agents.The issue of combined liver/kidney transplantation in LT candidates with renal failure is beyond the scope of this review and will not be considered herein.Immunosuppression for patients in the early post-operative periodThe issue of early renal dysfunction after liver transplantationAcute post-operative renal injury frequently occurs after LT [1Fraley D.S. Burr R. Bernardini J. Angus D. Kramer D.J. Johnson J.P. Impact of acute renal failure on mortality in end-stage liver disease with or without transplantation.Kidney Int. 1998; 54: 518-524Crossref PubMed Scopus (179) Google Scholar, 2McCauley J. Van Thiel D.H. Starzl T.E. Puschett J.B. Acute and chronic renal failure in liver transplantation.Nephron. 1990; 55: 121-128Crossref PubMed Scopus (172) Google Scholar, 3Lima E.Q. Zanetta D.M. Castro I. Massarollo P.C. Mies S. Machado M.M. et al.Risk factors for development of acute renal failure after liver transplantation.Ren Fail. 2003; 25: 553-560Crossref PubMed Scopus (106) Google Scholar, 4Bilbao I. Charco R. Balsells J. Lazaro J.L. Hidalgo E. Llopart L. et al.Risk factors for acute renal failure requiring dialysis after liver transplantation.Clin Transpl. 1998; 12: 123-129PubMed Google Scholar, 5Cabezuelo J.B. Ramirez P. Rios A. Acosta F. Torres D. Sansano T. et al.Risk factors of acute renal failure after liver transplantation.Kidney Int. 2006; 69: 1073-1080Crossref PubMed Scopus (232) Google Scholar, 6Karie-Guigues S. Janus N. Saliba F. Dumortier J. Duvoux C. Calmus Y. et al.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. 2009; 15: 1083-1091Crossref PubMed Scopus (62) Google Scholar], The high frequency of acute renal dysfunction results from variable, multi-factorial insults to the kidney, including pre-existing hepato-renal syndrome, the use of nephrotoxic antimicrobial agents and, obviously, the use of CNI immediately after LT. In fact, one of the strongest predictors is the dose and level of CNI in the early post-transplantation period [7Guitard J. Cointault O. Kamar N. Muscari F. Lavayssiere L. Suc B. et al.Acute renal failure following liver transplantation with induction therapy.Clin Nephrol. 2006; 65: 103-112Crossref PubMed Scopus (62) Google Scholar, 8Gonwa T.A. Mai M.L. Melton L.B. et al.End-Stage Renal Disease [ESRD] after Orthotopic Liver Transplantation [OLTX] using calcineurin-based imminotherapy risk of development and treatment.Transplantation. 2001; 72: 1934-1939Crossref PubMed Scopus (429) Google Scholar]. An important objective in the early post-operative period is, therefore, to optimize the immunosuppressive regimen in order to protect kidney function and prevent long-term consequences.Depending on the criteria used to define "acute renal failure," post-operative renal injury has been reported in 17–94% of patients undergoing LT [1Fraley D.S. Burr R. Bernardini J. Angus D. Kramer D.J. Johnson J.P. Impact of acute renal failure on mortality in end-stage liver disease with or without transplantation.Kidney Int. 1998; 54: 518-524Crossref PubMed Scopus (179) Google Scholar, 2McCauley J. Van Thiel D.H. Starzl T.E. Puschett J.B. Acute and chronic renal failure in liver transplantation.Nephron. 1990; 55: 121-128Crossref PubMed Scopus (172) Google Scholar, 3Lima E.Q. Zanetta D.M. Castro I. Massarollo P.C. Mies S. Machado M.M. et al.Risk factors for development of acute renal failure after liver transplantation.Ren Fail. 2003; 25: 553-560Crossref PubMed Scopus (106) Google Scholar, 4Bilbao I. Charco R. Balsells J. Lazaro J.L. Hidalgo E. Llopart L. et al.Risk factors for acute renal failure requiring dialysis after liver transplantation.Clin Transpl. 1998; 12: 123-129PubMed Google Scholar, 5Cabezuelo J.B. Ramirez P. Rios A. Acosta F. Torres D. Sansano T. et al.Risk factors of acute renal failure after liver transplantation.Kidney Int. 2006; 69: 1073-1080Crossref PubMed Scopus (232) Google Scholar, 6Karie-Guigues S. Janus N. Saliba F. Dumortier J. Duvoux C. Calmus Y. et al.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. 2009; 15: 1083-1091Crossref PubMed Scopus (62) Google Scholar]. Using the RIFLE (Risk–Injury–Failure–Loss–Endstage) criteria (Table 1) for acute renal dysfunction, renal "injury" (increase in serum creatinine ⩾2.0 × baseline or decrease in GFR ⩾50%) was observed in 41.5% of the patients in the first month post-LT [[7]Guitard J. Cointault O. Kamar N. Muscari F. Lavayssiere L. Suc B. et al.Acute renal failure following liver transplantation with induction therapy.Clin Nephrol. 2006; 65: 103-112Crossref PubMed Scopus (62) Google Scholar]. In two studies, in which renal failure was defined by an increase in serum creatinine ⩾50% above baseline values, the incidence of renal failure was 42% and 48% [5Cabezuelo J.B. Ramirez P. Rios A. Acosta F. Torres D. Sansano T. et al.Risk factors of acute renal failure after liver transplantation.Kidney Int. 2006; 69: 1073-1080Crossref PubMed Scopus (232) Google Scholar, 6Karie-Guigues S. Janus N. Saliba F. Dumortier J. Duvoux C. Calmus Y. et al.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. 2009; 15: 1083-1091Crossref PubMed Scopus (62) Google Scholar].Table 1The acute dialysis quality initiative (ADQI) criteria for the definition and classification of acute kidney injury: the RIFLE (Risk–Injury–Failure–Loss–Endstage renal disease) criteria⁎In Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acute Dialysis Quality Initiative workgroup: acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–R212..RIFLE classification is an attempt to define the presence or absence of the clinical syndrome of acute kidney injury in a given patient, and to describe the severity of this syndrome. In Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acute Dialysis Quality Initiative workgroup: acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–R212. Open table in a new tab Severe forms of acute renal "failure" (RIFLE) requiring renal replacement therapy (RRT) have been reported in 6.5–18.3% [9Gonwa T.A. Mai M.L. Melton L.B. Hays S.R. Goldstein R.M. Levy M.F. et al.Renal replacement therapy and orthotopic liver transplantation: the role of continuous veno-venous hemodialysis.Transplantation. 2001; 71: 1424-1428Crossref PubMed Scopus (135) Google Scholar, 10Wyatt C.M. Arons R.R. The burden of acute renal failure in nonrenal solid organ transplantation.Transplantation. 2004; 78: 1351-1355Crossref PubMed Scopus (54) Google Scholar, 11Contreras G. Garces G. Quartin A.A. Cely C. LaGatta M.A. Barreto G.A. et al.An epidemiologic study of early renal replacement therapy after orthotopic liver transplantation.J Am Soc Nephrol. 2002; 13: 228-233PubMed Google Scholar, 12Singh N. Gayowski T. Wagener M.M. Post transplantation dialysis-associated infections: morbidity and impact on outcome in liver transplant recipients.Liver Transpl. 2001; 7: 100-105Crossref PubMed Scopus (35) Google Scholar, 4Bilbao I. Charco R. Balsells J. Lazaro J.L. Hidalgo E. Llopart L. et al.Risk factors for acute renal failure requiring dialysis after liver transplantation.Clin Transpl. 1998; 12: 123-129PubMed Google Scholar, 13Rueggeberg A. Boehm S. Napieralski F. Mueller A.R. Neuhaus P. Falke K.J. et al.Development of a risk stratification model for predicting acute renal failure in orthotopic liver transplantation recipients.Anaesthesia. 2008; 63: 1174-1180Crossref PubMed Scopus (48) Google Scholar] of cases, usually early, within the first week post-LT. In this setting, acute renal failure results from major post-operative stresses frequently associated with acute tubular necrosis, including prolonged hypotension, sepsis or septic shock, sustained pre-renal failure, primary graft non-function, or delayed function of the liver.Post-operative renal injury is responsible for significant mid- and long-term consequences and impacts both on kidney function and survival. Renal replacement therapy has consistently been associated with a significant reduction in 1-year survival compared to patients not requiring RRT: 1-year survival in RRT patients is close to 50% (Fig. 1) [9Gonwa T.A. Mai M.L. Melton L.B. Hays S.R. Goldstein R.M. Levy M.F. et al.Renal replacement therapy and orthotopic liver transplantation: the role of continuous veno-venous hemodialysis.Transplantation. 2001; 71: 1424-1428Crossref PubMed Scopus (135) Google Scholar, 12Singh N. Gayowski T. Wagener M.M. Post transplantation dialysis-associated infections: morbidity and impact on outcome in liver transplant recipients.Liver Transpl. 2001; 7: 100-105Crossref PubMed Scopus (35) Google Scholar]. Among survivors, RRT is considered a significant predictor of impaired renal function in the long term, with a more than 2-fold increase in the risk of chronic renal failure [[14]Ojo A.O. Held P.J. Port F.K. et al.Chronic renal failure after transplantation of a nonrenal organ.N Engl J Med. 2003; 349: 931Crossref PubMed Scopus (1750) Google Scholar]. Early acute renal injury not requiring RRT is also considered a major contributor to the long-term risk of chronic kidney disease [8Gonwa T.A. Mai M.L. Melton L.B. et al.End-Stage Renal Disease [ESRD] after Orthotopic Liver Transplantation [OLTX] using calcineurin-based imminotherapy risk of development and treatment.Transplantation. 2001; 72: 1934-1939Crossref PubMed Scopus (429) Google Scholar, 15Ojo A.O. Renal disease in recipients of non renal solid organ transplantation.Semin Nephrol. 2007; 27: 498-507Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 16Velidedeoglu E. Bloom R.D. Crawford M.D. Desai N.M. Campos L. Abt P.L. et al.Early kidney dysfunction post liver transplantation predicts late chronic kidney disease.Transplantation. 2004; 77: 553-556Crossref PubMed Scopus (60) Google Scholar]. In most studies, early elevation in serum creatinine at 1, 3, or 6 months post-LT was an independent predictor of chronic renal failure [8Gonwa T.A. Mai M.L. Melton L.B. et al.End-Stage Renal Disease [ESRD] after Orthotopic Liver Transplantation [OLTX] using calcineurin-based imminotherapy risk of development and treatment.Transplantation. 2001; 72: 1934-1939Crossref PubMed Scopus (429) Google Scholar, 15Ojo A.O. Renal disease in recipients of non renal solid organ transplantation.Semin Nephrol. 2007; 27: 498-507Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 16Velidedeoglu E. Bloom R.D. Crawford M.D. Desai N.M. Campos L. Abt P.L. et al.Early kidney dysfunction post liver transplantation predicts late chronic kidney disease.Transplantation. 2004; 77: 553-556Crossref PubMed Scopus (60) Google Scholar]. And in a recent retrospective study [[17]Schmitz V. Laudi S. Moeckel F. et al.Chronic renal dysfunction following liver transplantation.Clin Transplant. 2008; 22: 333Crossref PubMed Scopus (40) Google Scholar] of 1075 patients, the onset of chronic renal dysfunction within the first year after LT was even correlated with reduced survival.Limiting early insults of any kind to the kidney and especially CNI toxicity is, therefore, of major importance in order to preserve renal function and survival in the long-term. With respect to this, understanding the mechanism of CNI nephrotoxicity is essential.Mechanism of acute CNI renal toxicity and the relationship with end-stage liver diseaseCyclosporine and Tac are two CNI which share a similar mechanism of action, as well as a pattern of nephrotoxicity. Acute CNI nephrotoxicity is caused by an intense, predominantly afferent, arteriolar vasoconstriction (Fig. 2) which thereby alters renal hemodynamics (reviewed in [18Olyaei A.J. Angelo M. de Mattos A.M. William M. Bennett W.M. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies.Curr Opin Crit Care. 2001; 7: 384-389Crossref PubMed Scopus (257) Google Scholar, 19Bobadilla N.A. Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone.Am J Physiol Renal Physiol. 2007; 293: F2-F9Crossref PubMed Scopus (102) Google Scholar]. This pre-renal, dose-related, renal dysfunction results in an acute and reversible decrease in the glomerular filtration rate (GFR), renal blood flow, and urine output. The vasoconstriction is in part related to an imbalance in the release of vasodilator substances, such as prostaglandin E2 [[20]Perico N. Benigni A. Bosco E. Rossini M. Orisio S. Ghilardi F. et al.Acute cyclosporine A nephrotoxicity in rats: which role for renin–angiotensin system and glomerular prostaglandins?.Clin Nephrol. 1986; 25: S83-S88PubMed Google Scholar] or NO [[21]Bobadilla N.A. Tapia E. Franco M. Lopez P. Mendoza S. Garcia-Torres R. et al.Role of nitric oxide in renal hemodynamic abnormalities of cyclosporin nephrotoxicity.Kidney Int. 1994; 46: 773-779Crossref PubMed Scopus (93) Google Scholar], and increased vasoconstrictor factors, such as thromboxane A2, endothelin 1 [[22]Kon V. Sugiura M. Inagami T. Harvie B.R. Ichikawa I. Hoover R.L. Role of endothelin in cyclosporine-induced glomerular dysfunction.Kidney Int. 1990; 37: 1487-1491Crossref PubMed Scopus (359) Google Scholar], and angiotenisin II [[20]Perico N. Benigni A. Bosco E. Rossini M. Orisio S. Ghilardi F. et al.Acute cyclosporine A nephrotoxicity in rats: which role for renin–angiotensin system and glomerular prostaglandins?.Clin Nephrol. 1986; 25: S83-S88PubMed Google Scholar]. Local activation of the sympathetic nervous system may also contribute. Following discontinuation of CNI, renal function usually returns to baseline without any major histological or cytological abnormalities. However, in some instances, prolonged vasoconstriction may directly damage renal tubular cells causing acute tubular vacuolization (Fig. 3) or necrosis, with subsequent tubule-interstitial lesions and chronic/irreversible nephrotoxicity [[19]Bobadilla N.A. Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone.Am J Physiol Renal Physiol. 2007; 293: F2-F9Crossref PubMed Scopus (102) Google Scholar].Fig. 2Schematic representation of the pathophysiology of calcineurin inhibitors nephrotoxicity.Reprinted from Naesens et al. [[45]Naesens M. Kuypers D.R.J. Sarwal M. Calcineurin inhibitor nephrotoxicity.Clin L Am Soc Nephrol. 2009; 4: 481-508PubMed Google Scholar], with permission from the American Society of Nephrology.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3Renal injury after liver transplantation. Role of calcineurin inhibitors and other co-factors.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Immunosuppressive approaches to prevent acute renal dysfunctionPrevention of acute CNI nephrotoxicity can in principle be achieved by: (A) excluding CNI from immunosuppressive regimens; (B) delaying the introduction of CNI beyond the very early post-operative phase during which the kidney is particularly susceptible to CNI acute injury; and, (C) early minimization of CNI levels.Excluding CNI from immunosuppressionWithdrawing CsA in patients with HRS or significant renal dysfunction and replacement with Azathioprine and steroids was first proposed [[23]Gonwa T.A. Klintmalm G.B. Levy M. et al.Impact of pre-transplant renal function on survival after liver transplantation.Transplantation. 1995; 59: 361Crossref PubMed Scopus (382) Google Scholar] in the early nineties. Such an approach must be used with caution in the early post-operative phase because elimination of CNI even when substituted by more recent antiproliferative agents than Azathioprine, such as MPA has been associated with a notable rate of rejection [24Schlitt H.J. Barkmann A. Boker K.H. Schmidt H.H. Emmanouilidis N. Rosenau J. et al.Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study.Lancet. 2001; 357: 587-591Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 25Orlando G. Baiocchi L. Cardillo A. Iaria G. De Liguori Carino N. De Luca L. et al.Switch to 1.5 grams MPA monotherapy for CNI-related toxicity in liver transplantation is safe and improves renal function, dyslipidemia, and hypertension.Liver Transpl. 2007; 13: 46-54Crossref PubMed Scopus (61) Google Scholar] and even graft loss.Sirolimus and Everolimus are two mammalian targets of Rapamycin inhibitors (mTOR) which when given without CNI in patients with normal baseline renal function are not considered nephrotoxic. Yet, mTOR inhibitors are usually avoided in the immediate post-LT period. A pivotal study combining Sirolimus and Tacrolimus as a primary immunosuppressive regimen demonstrated a significant reduction in 1-year survival because of an unexpected incidence of infections and vascular thrombotic complications. In addition, wound healing complications may also be caused by the antiproliferative effects of this class of agents. For these reasons, very early use of mTOR inhibitors post-LT cannot yet be recommended. However, a study in 145 liver transplant recipients on maintenance regimens supported that concentration-controlled Everolimus allows for the elimination of CNI without increasing the risk of acute rejection [[26]De Simone P. Metselaar H.J. Fischer L. Dumortier J. Boudjema K. Hardwigsen J. et al.Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial.Liver Transpl. 2009; 15: 1262-1269Crossref PubMed Scopus (124) Google Scholar]. Early introduction of mTOR inhibitors, 4 weeks post-LT, followed by early reduction or discontinuation of CNI may provide superior renal function compared to CNI-based standard therapy and, is currently under investigation (Clinical Trials.gov identifier: NCT00622869).Another option which has achieved encouraging results in kidney transplantation [[27]Vincenti F. Larsen C. Durrbach Wekerle.T. Nashan B. Blancho G. Lang P. et al.Costimulation blockade with belatacept in renal transplantation.N Engl J Med. 2005; 353: 770-781Crossref PubMed Scopus (744) Google Scholar] is the blockade of the T-cell co-stimulation pathway. Belatacept is a fusion protein derived from CTLA4-Ig which blocks the interactions of CD28 with CD80 and CD86 with a 10-fold greater inhibition of T-cell activation in vitro as compared with CTLA4-Ig alone. In kidney transplantation, a Phase II study involving 218 recipients of de novo renal allografts compared the efficacy of Belatacept to CsA as a maintenance immunosuppressant together with Basiliximab induction, steroids, and MPA [[27]Vincenti F. Larsen C. Durrbach Wekerle.T. Nashan B. Blancho G. Lang P. et al.Costimulation blockade with belatacept in renal transplantation.N Engl J Med. 2005; 353: 770-781Crossref PubMed Scopus (744) Google Scholar]. Belatacept-based therapy (intravenous infusion every 4 or 8 weeks) showed similar efficacy in preventing acute rejection at 6 months versus CsA-based treatment: 6–7% for Belatacept versus 8% for CsA. Furthermore, Belatacept-treated patients showed a significant improvement in renal function at one year compared with CsA-treated patients (63 ml/mn versus 53.5 ml/mn/1.73 m2). Whether such a beneficial impact on renal function can be achieved in LT recipients on maintenance Belatacept therapy is currently being investigated (Belatacept in liver transplantation; Clinical Trials.gov identifier: NCT00555321).Delaying introduction of CNI (Table 2)The challenge of such an approach is to ensure adequate immunosuppression despite delayed introduction of CNI. To achieve this goal, induction therapy with anti-lymphocyte/thymocyte antibody preparations or anti-interleukin-2-receptor antibodies, with or without MPA have been proposed (Table 2). This approach can be particularly useful in instances where pre- or immediate post-LT renal function is significantly altered.Table 2Impact of induction therapies and delayed introduction of calcineurin inhibitors on renal function after 28Soliman T. Hetz H. Burghuber C. Gyori G. Silberhumer G. Steininger R. et al.Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation.Liver Transpl. 2007; 13: 1039-1044Crossref PubMed Scopus (71) Google Scholar, 30Bajjoka I. Hsaiky L. Brown K. Abouljoud M. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors.Liver Transpl. 2008; 14: 66-72Crossref PubMed Scopus (40) Google Scholar, 31Lin C. Chuang F.R. Lee C.H. et al.The renal-sparing efficacy of basiliximab in adult living donor liver transplantation.Liver Transpl. 2005; 11: 1258-1264Crossref PubMed Scopus (50) Google Scholar, 32Yoshida E.M. Marotta P.J. Greig P.D. Kneteman N.M. Marleau D. Cantarovich M. et al.Evaluation of renal function in liver transplant recipients receiving daclizumab [Zenapax], mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial.Liver Transpl. 2005; 11: 1064-1072Crossref PubMed Scopus (116) Google Scholar, 33Neuberger J.M. Mamelok R.D. Neuhaus P. Pirenne J. Samuel D. Isoniemi H. et al.The ReSpECTStudy Group. Delayed Introduction of Reduced-Dose Tacrolimus, and Renal Function in Liver Transplantation: The 'ReSpECT' Study.Am J Transplant. 2009; 9: 327-336Crossref PubMed Scopus (207) Google Scholar.[36]Farkas S.A. Schnitzbauer A.A. Kirchner G. Obed A. Banas B. Schlitt H.J. Calcineurin inhibitor minimization protocols in liver transplantation.Transpl Int. 2009; 22: 49-60Crossref PubMed Scopus (70) Google ScholarCNI, calcineurin inhibitors; IL 2R Ab, IL2 receptors Antibodies; ATG, anti-thymocyte globulins; MMF, mycophenolate mofetil. Overall, delayed-reduced introduction of CNI, in combination with induction therapy + MMF was associated with an improvement in renal function without increasing the risk of rejection in the short and mid-term. Open table in a new tab Anti-lymphocyte antibodiesIn a retrospective study [[28]Soliman T. Hetz H. Burghuber C. Gyori G. Silberhumer G. Steininger R. et al.Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation.Liver Transpl. 2007; 13: 1039-1044Crossref PubMed Scopus (71) Google Scholar] comparing 129 patients receiving standard CNI, with 262 patients receiving 3-day induction therapy with Thymoglobulin (2.5 mg/kg/d) followed by CNI introduction as the local standard prophylactic treatment, Soliman and colleagues reported better renal function at 1-year in the Thymoglobulin induction group (GFR: 81 versus 72 ml/min, p= 0.02). In addition, Thymoglobulin patients experienced less frequent rejection with similar 1-year survival and a similar incidence of de novo tumors. Interestingly, the same group recently reported that a longer (10-day) Thymoglobulin-based induction therapy [[29]Soliman T. Hetz H. Burghuber C. Györi G. Silberhumer G. Steininger R. et al.Short-term versus long-term induction therapy with antithymocyte globulin in orthotopic liver transplantation.Transpl Int. 2007; 20: 447-452Crossref PubMed Scopus (23) Google Scholar] was associated with an increased risk of infection, supporting the concept that the best risk–benefit ratio was achieved with the short induction phase. Similar results were observed by Bajjoka et al. [[30]Bajjoka I. Hsaiky L. Brown K. Abouljoud M. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors.Liver Transpl. 2008; 14: 66-72Crossref PubMed Scopus (40) Google Scholar]. In this study, all the patients had post-operative renal dysfunction defined by the need for hemodialysis or a creatinine >1.5 mg/dl, and received MPA. Anti-thymocyte globulin (0.5–1 mg/kg/d) was given for a maximum of 5 days or until creatinine had decreased <1.2 mg/dl. Delayed CNI initiation after anti-thymocyte globulin induction was associated with a significant improvement in renal function with a higher estimated glomerular filtration rate (57.4 versus 43.7 ml/min/1.73 m2, p<0.001) and less dependence on dialysis (0.8% versus 13%, p<0.001) at 12 months post-transplant, with no impact on CMV infection or severity of HCV recurrence.Anti-interleukin-2-receptor antibodiesWhen complexed with anti-IL2 receptor antibodies, IL-2 receptors on T-lymphocytes are no longer available for IL-2 binding, and the proliferation of associated T-lymphocytes is inhibited. The duration of IL-2 receptor saturation in adults is longer than 4 weeks and several studies have tested whether a delayed introduction of CNI after Daclizumab or Basiliximab induction therapy was beneficial to kidney function. In a prospective non-randomized open label study [[31]Lin C. Chuang F.R. Lee C.H. et al.The renal-sparing efficacy of basiliximab in adult living donor liver transplantation.Liver Transpl. 2005; 11: 1258-1264Crossref PubMed Scopus (50) Google Scholar], 47 consecutive living donor LT recipients were treated either with Basiliximab induction therapy + MPA and delayed introduction of Tacrolimus, or with conventional CNI + MPA therapy. Basiliximab was preferentially used in the sickest patients at transplantation and in those with significant blood loss. In such cases, Tac was introduced as a median of 36 h post-LT [24–108 h]. The creatinine clearance rate was higher (median 72 versus 57 ml/min, p= 0.04) and the incidence of renal insufficiency was lower in the induction group (26% versus 67%, p<0.01) at three months post-transplant.A beneficial impact of delayed introduction of CNI on renal function in patients receiving Daclizumab induction therapy has also been reported in two randomized controlled studies [32Yoshida E.M. Marotta P.J. Greig P.D. Kneteman N.M. Marleau D. Cantarovich M. et al.Evaluation of renal function in liver transplant recipients receiving daclizumab [Zenapax], mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial.Liver Transpl. 2005; 11: 1064-1072Crossref PubMed Scopus (116) Google Scholar, 33Neuberger J.M. Mamelok R.D. Neuhaus P. Pirenne J. Samuel D. Isoniemi H. et al.The ReSpECTStudy Group. Delayed Introduction of Reduced-Dose Tacrolimus, and Renal Function in Liver Transplantation: The 'ReSpECT' Study.Am J Transplant. 2009; 9: 327-336Crossref PubMed Scopus (207) Google Scholar] (Table 2) without increasing the risk of rejection. In both studies, Daclizumab was given in combination with MPA, followed by delayed introduction of Tac at normal or even reduced doses. In the Yoshida and colleagues study [[32]Yoshida E.M. Marotta P.J. Greig P.D. Kneteman N.M. Marleau D. Cantarovich M. et al.Evaluation of renal function in liver transplant recipients receiving daclizumab [Zenapax], mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial.Liver Transpl. 2005; 11: 1064-1072Crossref PubMed Scopus (116) Google Scholar], GFR calculated by the Modification of Diet in Renal Disease [[34]Levey A.S. Bosch J.P. Lewis J.B.