Strategies to prevent or reduce acute and chronic kidney injury in liver transplantation

Authors

  • Fuat H. Saner,

    1. Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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  • Vito R. Cicinnati,

    1. Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
    2. Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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  • Georgios Sotiropoulos,

    1. Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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  • Susanne Beckebaum

    1. Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
    2. Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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Susanne Beckebaum, Interdisciplinary Liver Transplant Unit, University Hospital Essen, OPZ II, Ebene A1, Hufelandstr. 55, 45122 Essen, Germany
Tel:+49 201 723 1104
Fax:+49 201 723 1113
e-mail: susanne.beckebaum@uni-due.de

Abstract

Acute kidney injury (AKI) has a major impact on short- and long-term survival in liver transplant (LT) patients. There is no currently accepted uniform definition of AKI, which would facilitate standardization of the care of patients with AKI and to improve and enhance collaborative research efforts. New promising biomarkers such as neutrophil gelatinase-associated lipocalin or kidney injury molecule-1 have been developed for the prevention of delayed AKI treatment. Early dialysis has been shown to be beneficial in patients with AKI stage III according to the classification of the Acute Kidney Injury Network, whereas treatment with loop diuretics or dopamine is associated with worse outcome. The mainstay for the prevention of AKI seems to be avoidance of volume depletion and maintenance of a mean arterial pressure >65 mmHg. Although the aetiology of chronic kidney disease in transplant recipients may be multifactorial, calcineurin-inhibitor (CNI)-induced nephrotoxicity significantly contributes to the development of renal dysfunction over time after LT. The delayed introduction of CNI at minimal doses has shown to be safe and effective for the preservation of kidney function. Other strategies to overcome CNI nephrotoxicity include CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil or the mammalian target of rapamycin inhibitor-based immunosuppressive regimens. However, CNI avoidance may bear a higher rejection risk. Thus, more results from randomized-controlled studies are urgently warranted to determine which drug combinations are the most beneficial approaches for the potential introduction of CNI-free immunosuppressive regimens.

Following liver transplantation (LT), patients are at a major risk of developing renal replacement therapy (RRT)-dependent-acute kidney injury (AKI) in the early post-operative phase. The reported incidence of AKI after LT widely ranges between 8% and 78% (1, 2). The main risk factors include preoperative hepatorenal syndrome, extended caval cross clamping time, perioperative hypotension and large volume transfusion. Possible consequences of AKI are progression of pre-existing chronic kidney disease to advanced stage renal disease and/or further impairment of kidney function because of calcineurin inhibitor (CNI) nephrotoxicity, hypertension and metabolic disorders.

The incidence of chronic renal dysfunction has been reported in up to 70% of LT patients (3, 4). End-stage renal disease has been described to occur in 18% of patients during a follow-up of 13 years after LT (5). Besides CNI, which still represents the backbone of most maintenance immunosuppressive regimens, a broad spectrum of drugs are currently available including antibodies to lymphocyte, antimetabolites and inhibitors of the mammalian target of rapamycin (mTOR). Current protocols often use several drugs with different mechanisms of action allowing CNI dosage reduction or avoidance and thereby reducing renal side effects.

This review focuses on the preventive strategies for AKI, early diagnosis of acute renal dysfunction and therapeutic interventions for renal recovery. Furthermore, we discuss current immunosuppressive agents and regimens that have been evaluated to overcome CNI-related nephrotoxicity over time after LT.

Pretransplant renal dysfunction and definition of acute kidney injury

Pretransplant renal dysfunction because of the hepatorenal syndrome is an important risk factor for the development of AKI after LT. Other main causes of kidney failure before LT include IgA nephropathy, hepatitis B and C virus-related glomerulonephritis, diabetic and hypertensive nephropathy and non-diabetic glomerulosclerosis (6). The hepatorenal syndrome is a severe and common complication of patients with advanced cirrhosis and a consequence of splanchnic arterial vasodilation, a reduction in cardiac output and activation of vasoconstrictor systems (7). Renal failure may be rapidly progressive (type I hepatorenal syndrome) or may develop more slowly (type II) (8). Patients with type I HRS are reported with 90% mortality within 8 weeks, whereas 35% of patients with type II HRS will survive 1 year (9). The bottom line of the treatment of HRS is the use of vasoconstrictors and volume replacement. The most-used vasoconstrictors are vasopressin analogues such as ornipressin (10) and terlipressin (11).

The effect of terlipressine with or without volume replacement with albumin has been investigated previously in patients with cirrhosis (12, 13). Results have shown that the reversal of HRS in patients with volume replacement was significantly better as compared with patients who received terlipressine alone. However, the 90-day survival could not be improved with this treatment, which indicates that LT is the only causative treatment in these patients. The perioperative use of terlipressin has also been shown to impede the early post-transplant impairment of kidney function in patients with chronic liver disease undergoing LT (14).

Trawale et al. (6) evaluated the results of renal biopsy in cirrhotic patients with impaired kidney function. The authors reported that 40% of the specimens showed very complex renal lesions, including acute tubulointerstitial lesions, interstitial fibrosis with tubular atrophy, osmotic lesions and arteriolar lesions. This study reveals that kidney impairment in the majority of LT candidates is very complex and requires a meticulous pre-operative work-up for the best peri- and post-operative treatment strategy.

More than 35 different definitions of AKI are published in the literature (15), which makes comparison of the results from clinical trials of prevention and treatment of AKI difficult or often impossible. However, most classifications have used common parameters such as serum creatinine (SCr) and urine output.

The Acute Dialysis Qualitative Initiative (ADQI) group (16) established the Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease (RIFLE) score and classified AKI into 5 degrees of severity based on the glomerula filtration rate, SCr, urine output and 2 clinical outcomes (Table 1). Recently, the Acute Kidney Injury Network has modified the RIFLE criteria (17). The group stratified only three stages of AKI according to an increase of SCr and/or a decrease of urine output. The stages ‘loss’ and ‘end-stage kidney disease’ were removed from the original RIFLE score and patients dependent on RRT were included in stage 3. Further changes of the modified version are depicted in Table 2.

Table 1.  Classification of acute kidney injury according to the Acute Dialysis Qualitative Initiative (ADQI)
Classification of AKICreatinine increaseUrine output
  1. Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease (RIFLE) classification of acute kidney injury proposed by ADQI. A patient may fulfil the criteria through changes in serum creatinine increase, changes in urine output or in both.

  2. AKI, acute kidney injury; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; h, hour(s).

Risk50–100% or GFR decrease >25%<0,5 ml/kg/h for 6 h
Injury100–200% or GFR decrease >50%<0,5 ml/kg/h for 12 h
Failure>200% or GFR decrease >75%<0,3 ml/kg/h for 24 h or anuria for 12 h
LossComplete loss of kidney function; >4 weeks dialysis
ESKDEnd stage kidney disease; >3 months dialysis
Table 2.  Classification system of the Acute Kidney Injury Network (AKIN)
AKI stageSerum-creatinine criteriaUrine output criteria
  1. AKI, acute kidney injury; h, hour(s).

1≥ 0.3 mg/dl or 150–200% increase from baseline<0,5 ml/kg/h for >6 h
2>200–300% (>2- to three-fold) increase from baseline<0,5 ml/kg/h for >6 h
3>300% (>3-fold) increase from baseline or serum creatinine ≥4 mg/dl<0,3 ml/kg/h for >24 h or anuria for>12 h

Biomarkers for the early detection of acute kidney injury

Neutrophil gelatinase-associated lipocalin (NGAL) is as a novel biomarker for the diagnosis of a very early stage of AKI. After ischaemia-reperfusion, NGAL is upregulated in distal tubular cells and secreted in the urine (18). Plasma-NGAL has been evaluated in different clinical scenarios, including LT patients (19). Recently, urinary NGAL was also found to be a reliable marker of AKI in the LT setting (20).

Interleukin-18 (IL-18) is a proinflammatory cytokine and a member of the IL-1 cytokine superfamily. It is released into the urine proximal tubules injured by ischaemia and urinary IL-18 elevation (21) predicts AKI about 24 h (h) earlier than SCr. In a prospective clinical trial, IL-18 and NGAL were identified as predictive biomarkers for delayed graft function in kidney transplant patients (22). Both NGAL and IL-18 levels were positively associated with the duration of AKI.

Kidney injury molecule-1 (KIM-1) is a protein that is expressed in the proximal tubule cells in patients with ischaemic or nephrotoxic AKI (23) and can be easily detected in the urine. In a clinical study with cardiothoracic patients, it has been shown that urinary KIM-1 levels were significantly higher 2 and 24 h after surgery in those (31%) who experienced AKI (24).

Cystatin C is a protease inhibitor that is synthetized and released by all nuclear cells (25). In critically ill patients, a 50% cystatin C increase predicts AKI 2 days before the increase of SCr (26). However, cystatin C seems to be more a sensitive marker of a reduction in the glomerular filtration rate (GFR) than that for AKI.

Risk factors of acute kidney injury

An adequate renal haemodynamic, in particular renal blood flow (RBF), is an important issue for preserving kidney function. Pre- and post-glomerular resistance is adjusted involving different vasoactive substances, including adenosine, adenosine triphosphate, renin and nitric oxide (27). RBF and GFR remain relatively constant despite fluctuating mean arterial pressures (MAP) (28). This is true for a MAP ranging between 70 and 95 mmHg (29, 30). Patients with MAP values of<70 mmHg experience a decrease of RBF and should be treated with adequate fluid resuscitation to avoid kidney failure (31).

A correlation has been shown between positive fluid balance and intra-abdominal hypertension (IAH) in LT patients (32). IAH can strongly affect kidney function by reducing the abdominal perfusion pressure (33). IAH may impair the systemic haemodynamic in general and in particular the kidney perfusion by decreasing MAP and impairing kidney outflow, which is a relevant step for AKI (33).

Most cases of post-operative AKI are related to renal hypoperfusion as a consequence to hypovolaemia, hypotension and cardiac dysfunction (34, 35). In LT patients, pre-operative existing hepato-renal syndrome, poor liver graft function and caval clamping time are additional risk factors that may contribute to post-operative AKI (36).

Strategies for the prevention and treatment of acute kidney injury

Plasma volume replacement and maintenance of renal perfusion

Despite the lack of adequate prospective randomized-controlled trials, it is widely known that volume depletion is a major risk factor for post-operative AKI (31, 37). There is an ongoing debate concerning the ideal fluid composition for volume resuscitation. Normal saline (NS) or potassium-free fluids are recommended for intravenous fluid therapy for patients with kidney failure (38). However, the administration of large volumes of NS is associated with the development of hyperchloraemic metabolic acidosis, which may cause hyperkalaemia (39). Moreover, the administration of large volumes of potassium-containing fluids such as lactated Ringer's (LR) solution may also cause hyperkalaemia in patients with AKI. A double-blinded randomized-controlled trial in patients undergoing kidney transplantation clearly indicated that the use of NS but not LR was associated with a significantly higher risk of acidosis (31% vs. 0% of patients) (40). In addition, hyperkalaemia was evident in 19% of patients in the NS group vs. 0% in the LR group.

Renal perfusion of septic patients has been shown to benefit from MAP values ≥65 mmHg (41). In the LT setting, volume replacement seems to be beneficial in patients with MAP<65 mmHg. There is an ongoing debate regarding which kind of fluids (colloid or crystalloids) should be administrated to improve haemodynamic disorders and to maintain renal perfusion. Aggressive crystalloid infusion may increase IAP and may contribute to renal perfusion impairment, whereas colloids maintain plasma volume more efficiently. In an animal study, haemodynamic balance was compared during prolonged pneumoperitoneum in piglets administered a crystalloid vs. a plasma volume-stabilizing fluid management regime (42). MAP and cardiac output remained within the normal range in the colloid group but not in the crystalloid group. However, these results need confirmation in multicentre human clinical trials.

In intensive care unit (ICU) patients, the use of 10% pentastarch (HES 200/0.5) was associated with higher rates of acute renal failure and renal-replacement therapy than LR (43). Another randomized-controlled trial revealed that HES (130/04) did not affect kidney function, when used for volume replacement in living donor LT patients (44). These conflicting results warrant further investigation with adequately powered randomized-controlled trials.

Management of fluid balance

The optimal fluid challenge in patients with AKI is unknown. Diuresis or fluid restriction may improve lung function but could impair extrapulmonary-organ perfusion. In a large European multicentre study, Payen and colleagues evaluated the impact of fluid balance on the outcome of patients with AKI. Among patients with oliguric AKI and those treated with RRT, the proportion of patients with a positive fluid balance was significantly higher in non-survivors as compared with survivors (45).

Bouchard et al. (46) evaluated fluid accumulation, survival and kidney recovery in critically ill patients. In patients with fluid overload, the mortality rate was significantly higher within 60 days. Among dialysed patients, survivors had significantly lower fluid accumulation compared with non-survivors after adjustments for dialysis modality and severity score.

It is as yet unclear when RRT should be started in ICU patients with advanced AKI. Interestingly, there is only one study in adults and several in paediatric patients that address this topic. The results indicated that early RRT seems to improve the outcome with respect to survival and length of ICU stay (45, 47–50). However, these studies are flawed by a retrospective design and data need to be confirmed in randomized-controlled trials.

Pharmacological intervention

Oliguria is caused by tubular obstruction with the accumulation of debris during kidney ischaemia. This obstruction leads to back leak of the GFR, which contributes to renal injury. Moreover, it is supposed that non-oliguric AKI may have a better outcome as compared with oliguric AKI.

Two meta-analyses evaluated the results of studies that addressed the role of loop diuretics in the prevention of AKI (51, 52). Both meta-analyses found no benefit for diuretics with respect to mortality, the incidence and requirement for RRT. In selected cases, the use of diuretics might be necessary in the management of volume overload, but there seems to be no role for diuretics in the prevention or the treatment of AKI.

The impact of dopamine on sodium excretion, GFR and RBF was evaluated in patients with congestive heart failure and in healthy volunteers (53). The authors found that sodium excretion increased significantly in both patients and normal subjects. Moreover, GFR and RBF increased in healthy volunteers, but not in the patients' cohort. Results from a large randomized-controlled trial and a meta-analysis have shown that the use of dopamine could not prevent AKI or RRT (54, 55).

There is also a widespread use of dopamine as a vasopressor in septic shock. In a recent prospective randomized large multicentre trial, the effect of dopamine was compared with norepinephrine in septic patients (56). There were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine [207 events (24.1%) vs. 102 events (12.4%), P<0.001]. A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death. Based on these data, there is evidence suggesting the use of norepinephrine instead of dopamine for the prevention of AKI. If the norepinephrine dose requirement exceeds 0.2 μg/kg/min, hydrocortisone should be considered. Suggestions for haemodynamic management are depicted in Fig. 1.

Figure 1.

 Suggestions for peri-/post-operative haemodynamic management in LT patients to avoid acute kidney injury. LT, liver transplantation; MAP, mean arterial pressure.

Fenoldopam, a selective dopamine-1-receptor agonist, has also been shown to increase GFR and RBF (57). Hypotension is a common side effect of fenoldopam. Without invasive blood pressure monitoring, it could impair AKI in LT patients, who may already suffer from severe systemic inflammatory response syndrome. In a placebo-controlled, randomized trial, fenoldopam failed to show any benefit in preventing AKI in cardiologic patients who underwent a cardiovascular intervention (58). In another single-centre placebo-controlled study, the incidence of AKI in the fenoldopam group was significantly lower compared with that of the placebo group (59). These conflicting results indicate that further studies are needed to clarify the role of fenoldopam in AKI.

Current immunosuppressive strategies to prevent or reduce calcineurin-inhibitor-related kidney dysfunction after liver transplantation

With the increasing life expectancy of LT recipients, chronic kidney disease has become a frequent complication among long-term survivors. Patients who developed post-LT chronic renal failure have a more than four-fold higher mortality than those who did not (60, 61). This issue is of even more concern in the model of end-stage liver disease (MELD) era, with a high proportion of patients with elevated creatinine values or on RRT at the time of LT (62). The risk factors for post-transplant chronic renal failure include hepatorenal syndrome, diabetes mellitus, hypertension, HCV infection, female gender and chronic kidney dysfunction before LT (60). Furthermore, chronic CNI-related kidney dysfunction including arteriolar hyalinosis, tubular atrophy, interstitial fibrosis and glomerular sclerosis is observed in most LT recipients with long-term CNI therapy (63).

Despite CNI-related parenchymal damage, various clinical trials have demonstrated that CNI dose reduction or discontinuation results in an improvement of renal function in the majority of LT patients, thus suggesting a partly dose-dependent nephrotoxic effect and reversible functional kidney damage (64).

Calcineurin-inhibitor-reduced immunosuppressive protocols

Mycophenolate mofetil and minimal dose calcineurin-inhibitor therapy

Increasing concerns of chronic renal dysfunction associated with long-term CNI therapy in up to 80% of LT recipients have resulted in the implementation of more or less aggressive CNI-sparing immunosuppressive regimens. CNI minimization and introduction of mycophenolate mofetil (MMF) is a frequently applied approach in LT patients to reduce CNI-related nephrotoxicity (65–67).

Mycophenolate mofetil is a morpholinoethyl ester prodrug of mycophenolic acid (MPA), an inhibitor of inositol-monophosphate dehydrogenase that catalyses the rate-limiting step in de novo purine biosynthesis leading to the suppression of T and B lymphocyte proliferation. MMF virtually lacks drug-related nephrotoxicity and does not increase cardiovascular risk. Several studies comprising immune and non-immune-mediated renal disease have provided evidence that MMF is effective in reversing structural changes in the kidney (68, 69). Some studies have demonstrated that MMF directly exerts protective effects against inflammation and fibrosis progression; suggested protective mechanisms include modification of the migratory and functional properties of fibroblasts, reduced nitric oxide production with subsequent suppressed allograft injury via interactions with superoxides, enhanced expression of MMP-1, deletion of antigen-specific T cells and reduction of inflammatory cytokine synthesis (70).

Gastrointestinal (GI) complaints and haematological changes such as leucopenia, anaemia and/or thrombocytopenia are the most important side effects associated with MMF therapy, but do not require drug discontinuation in the majority of patients (71). MPA monitoring is recommendable in the early phase after LT, since exposure to MPA has been shown to be low in a considerable proportion of patients during the first post-operative months (72). Therapeutic drug monitoring may also be taken into consideration in LT recipients with haematological or GI side effects, frequently occurring infectious complications or chronic renal disease. An enteric-coated formulation of MPA was developed to decrease GI adverse events and, consequently, to improve patients' compliance and GI health-related quality of life. The Leuven transplant group (73) reported that conversion of LT recipients with GI complaints from MMF to equimolar doses of enteric-coated mycophenolate sodium reduced GI-related symptom burden and the frequency of stools. Similarly, several studies in kidney transplant recipients reported better tolerability of enteric-coated mycophenolate sodium (74, 75), whereas others (76, 77) have failed to demonstrate any reduction of side effects after converting MMF to enteric-coated mycophenolate sodium.

In a prospective randomized trial (78), LT recipients were administered MMF and reduced CNI (≥50% of initial dose) and were compared with MMF-free controls in which CNI doses could be reduced up to 75% of the initial dose. In the MMF/low-dose CNI group, there was a significant improvement in SCr values and creatinine clearance at month 12, whereas in the control group, there was no improvement of renal function.

In our prospective, randomized study (66), LT patients with renal dysfunction were randomized either to receive MMF, followed by a stepwise reduction of CNI with defined minimal CNI-trough levels (MMF group), or to continue their maintenance CNI dose (control group). The CNI dose was progressively tapered to achieve defined target trough levels as low as 2–4 ng/ml for tacrolimus (TAC) and 25–50 ng/ml for cyclosporine A (CSA). In the MMF group, renal function improved in two-thirds of the patients, remained stable in one third and impaired in only 2% after 12 months compared with the baseline values. In the control group, renal function tended to deteriorate during the study period.

Long-term follow-up data over 60 months have demonstrated a sustained renal response after conversion to reduced CNI and MMF therapy (79). Full-dose MMF medication and early conversion after LT were identified as independent predictors of persistent renal function improvement. Despite the lack of a comparable control group of patients receiving CNI monotherapy, the reported results suggest a favourable long-term outcome for LT patients administered MMF-based immunosuppression.

Calcineurin-inhibitor-delayed immunosuppressive protocols

De novo immunosuppression with MMF combined with induction therapy and delayed CNI introduction is another approach to reduce CNI-related nephrotoxicity especially in patients with a higher MELD score.

In a recent multicentre, prospective, randomized trial (The ReSpECT study), LT patients were randomized to either group A (standard-dose TAC and corticosteroids); group B (MMF 2 g/day, reduced-dose TAC and corticosteroids); or group C (daclizumab induction, MMF and TAC at reduced dose and delayed until the fifth day post-transplant and corticosteroids) (80). The estimated GFR significantly decreased by 23.61 in group A and did not significantly change in B and C respectively. Renal dialysis was required less frequently in group C vs. group A. Interestingly, biopsy-proven acute rejection (BPAR) rates were significantly lower in group C as compared with the standard group.

In another randomized clinical trial, a daclizumab/MMF/delayed low-dose TAC-based regimen was compared with a standard TAC/MMF regimen (81). In both study arms, corticosteroids were tapered over time. Statistically significant higher median GFR were found in the delayed CNI group, whereas acute rejection episodes were not statistically significant different in both groups. Similar results have been found in two retrospective studies in LT patients receiving thymoglobulin induction therapy and delayed initiation of CNI (82, 83).

Calcineurin-inhibitor-free immunosuppressive regimens

Withdrawal of calcineurin inhibitor and switch to mycophenolate mofetil monotherapy

In a large cohort of LT patients with severe CNI-induced side effects, potential renal function recovery was investigated upon complete CNI withdrawal and replacement by MMF monotherapy (84). The mean estimated GFR improved significantly after switch to MMF monotherapy, from 37±10 to 44.7±15 ml/min/1.73 m2 at 6 months, which equated to a benefit of+17.4% in renal function. Two out of 52 patients experienced acute rejection.

Similar results with respect to renal recovery have been reported in another study; however, 10% of the patients developed acute rejection and 2% showed chronic rejection (85). In another study conducted by Fairbanks and Thuluvath (86), MMF monotherapy was associated with an even higher risk of allograft rejection in 19% of LT recipients. Considering the results from available studies, MMF monotherapy is a very attractive option but the balance between efficacy and risk of rejection needs to be weighted (84, 86–89). Therefore, this therapeutic option should be restricted to patients with a low immunological risk. However, careful selection of those patients is challenging, since individual risk estimation of acute rejection by genetic and/or immunological factors is not yet clinically established. There is some evidence indicating that the percentages of circulating regulatory T cells (Treg) that play a pivotal role in the establishment of immunological allograft tolerance are reduced in CNI-treated patients (90). Treg function critically depends on calcineurin-dependent IL-2 production and CNI have been shown to interfere with Treg induction in a dose-dependent manner (91). We have previously shown that the circulating cytotoxic T lymphocyte effector pool diminished, whereas the proportion of CD4+CD25+Foxp3+Treg significantly increased over time in LT patients under combined low-dose CNI and MMF therapy as compared with CNI monotherapy (66). A recent study (92) indicated that switch from CNI to MMF therapy increases CD25 expression and the proportion of CD4+CD25+Foxp3+Treg. These results suggest that MMF may promote immunological tolerance in allografts.

Withdrawal of calcineurin inhibitor and switch to mammalian target of rapamycin monotherapy in de novo and stable liver transplant patients

Another approach to maintain renal preservation is the replacement of CNI by mTOR inhibitors such as sirolimus (SRL) or everolimus (EVR). The side-effects of mTOR inhibitors include increased incidence of wound infection and dehiscence, hepatic artery thrombosis, hyperlipidaemia, thrombocytopenia, leucopenia and anaemia.

Previous studies have shown conflicting results with respect to renal recovery or preservation upon mTOR-inhibitor-based therapy. A recent retrospective analysis of 57 LT recipients with CNI-related chronic kidney dysfunction could not demonstrate that CNI withdrawal and conversion to SRL therapy was superior in preserving renal function to CNI reduction alone (93). A retrospective review of 148 LT patients converted to SRL over 10 years after LT showed a significant improvement of the mean GFR from 59±29 ml/min at baseline to 72±39 ml/min after a median follow-up of 1006 days (94).

The few published prospective randomized-controlled studies investigating SRL- or EVR-based immunosuppression are flawed by small patient cohorts and rather short follow-up periods (95–97). In a recent prospective study including 21 patients with chronic renal dysfunction, conversion to EVL allowed CNI elimination in 95.2% of patients. No rejection episode occurred post-conversion during a mean follow-up of 19.8 months. Kidney function initially improved significantly at day 30, but failed to show an advantage after 3 and 6 months (98). The lack of significant improvements in renal function can be attributed to the delayed introduction of mTOR inhibitors and to concurrent aetiological factors of renal dysfunction such as diabetic or hypertensive nephropathies.

In a recently published randomized-controlled study, patients were treated with CSA for the first 10 days, then randomized to receive EVR plus CSA up to day 30 and then either continued on EVR monotherapy (EVR group) or maintained on CSA with or without MMF (control group) (97). One-year results showed that MDRD was significantly better in the EVR monotherapy group as compared with the control group. Results from two multicentre, randomized, phase III studies (ClinicalTrials.gov Identifier: NCT00378014; NCT00622869) comparing an EVL-based regimen vs. a CNI-based regimen in de novo LT recipients will provide further information with respect to the role of the mTOR inhibitor in renal preservation after LT.

Combined mycophenolate mofetil and mammalian target of rapamycin inhibitor immunosuppression

To date, very limited information is available from studies investigating combined MMF and mTOR inhibitor therapy in LT patients (99, 100).

Interestingly, it has been shown that comedication with SRL or CSA differently affects MPA exposure in kidney transplant patients (101). CSA but not SRL inhibits the enterohepatic recirculation of MPA, resulting in 4.4-fold lower dose-adjusted MPA trough levels and 50% lower MPA daily exposure.

The results from a prospective, open labelled study of a CNI-free maintenance regimen with MMF and SRL were presented on the ATC 2009 (100). The mean time from transplant to study entry was 53.9±12.8 days in the MMF/SRL group and 51.8±11.3 days in the MMF/CNI control group. The mean GFR increase was significantly higher in the MMF/SRL group as compared with the control group (19.7±40.6% and 1.2±39.9, P<0.001) at month 12 (100). The BPAR rate was significantly higher in the MMF/SRL group (12.2% and 4.1%, P=0.014) but was not associated with a higher rate of graft loss.

The results from a prospective open-label, multicentre, randomized trial to investigate the switch from an ATG induction plus CSA/MMF/steroid regimen to an SRL/MMF/steroid regimen 10–24 days after renal transplantation demonstrated significantly better SCr and GFR values in the SRL-based treatment group as compared with the CSA/MMF/steroid control group (102). Of note, patient and graft survival and incidence of BPAR after conversion were not significantly different in both the groups.

The group from Regensburg initiated a single-arm pilot study to determine the safety and efficacy of a CNI-free combination therapy [basiliximab induction/MPA and delayed (10 days post-transplant) SRL] in patients with impaired renal function (GFR<50 ml/min and/or SCr>1.5 mg/dl) at LT (99). The study design stipulates that if at least 8 of 9 included patients do not present with steroid-resistant acute rejection within 30 days after LT, additional 20 patients will be included. The results from this ‘bottom-up’ immunosuppressive strategy need to be awaited to determine whether this strategy is an innovative concept to prevent or avoid further renal dysfunction during follow-up after LT.

However, a flaw of combined MMF and mTOR inhibitors therapy are agonistic side effects such as bone marrow suppression, which may limit its combined use in a substantial proportion of patients.

Conclusion

LT patients are at a risk of developing AKI post-operatively. The largest decline in renal function occurs during LT and the immediate post-operative period. Thus, intra- and peri-operative haemodynamic management is crucial to preserve long-term renal function.

The RIFLE score for the classification of AKI currently enhances the ability to design well-designed prospective studies without loss of comparability and develop collaborative networks. Application of new promising biomarkers may be useful for earlier detection and treatment of AKI. There are no evidence-based guidelines on optimal perioperative fluid management in LT patients; however, avoidance of dehydration and hypotension are useful strategies to avoid AKI. Early institution of RRT in LT patients with advanced AKI may have a beneficial impact on survival.

Emerging evidence suggests that AKI is accompanied by an increased risk for developing chronic kidney disease. Novel strategies to preserve renal function include reduced CNI protocols or CNI avoidance regimens. CNI discontinuation and replacement with MMF or SRL may have the potential to recover renal function. CNI delay with induction therapy for bridging the early post-operative phase should be considered especially in patients with high MELD scores.

Ancillary