Liver transplant (LT) recipients frequently experience chronic kidney disease (CKD), which significantly heightens the risk of mortality [1,2]. Among nonsolid organ transplant recipients, those who undergo LTs have the second-highest prevalence of CKD [2], and after LT, the cumulative occurrence of chronic kidney failure within a 5-year span amounted to 18% [1]. In this research, individuals with a measured glomerular filtration rate (GFR) below 30 mL/min exhibited a risk of death more than 2.6 times higher compared to those without CKD [3]. The aim of this study is to investigate the impact of perioperative risk factors and immunosuppressive regimens on the development of CKD following LT, with a focus on identifying strategies for early detection, modification of modifiable risk factors, and optimization of immunosuppression to preserve renal function and improve long-term outcomes.

The initial decline in kidney function following transplantation is typically viewed as multifaceted. Factors contributing to this decline include unresolved episodes of acute kidney injury (AKI) post-LT surgery, donor-related factors, and the administration of immunosuppressive medications, particularly calcineurin inhibitors (CNIs). AKI stands out as one of the most prevalent complications following LT, affecting nearly 50% of patients, with approximately 15% necessitating kidney replacement therapy. Additionally, the utilization of extended criteria liver grafts poses a potential risk factor for post-transplant CKD, correlating with elevated rates of CKD among recipients of such grafts [4]. In another study, recurrence of hepatocellular carcinoma and infections emerged as risk factors for CKD [5].

The gradual deterioration in kidney function following transplantation can be linked to various recipient factors, such as metabolic syndrome, diabetes, obesity, age, ethnicity, hepatitis C infection, and a previous history of malignancy. Since the inception of the model for end-stage liver disease (MELD) score in Jun 2016, Korea, individuals with elevated serum creatinine levels have been given priority for listing and subsequent LT and it’s quite common to observe the persistence and progression of CKD following LT [6].

There have been indications pointing towards maintenance immunosuppressive regimens as possible factors linked to the advancement of CKD within this population. The hypothesis suggests that the early administration of CNIs and their vasoconstrictive impact on the afferent arteriole could detrimentally affect kidneys experiencing AKI from various causes. It is presumed that the chronic vasoconstriction of kidney arterioles and associated endothelial damage contribute to the progression of kidney disease in transplant recipients [7].

Various predictive scoring systems have been developed in attempts to identify risk factors [8-10]. The primary focus should be directed towards early detection of risk factors, addressing modifiable ones, and minimizing perioperative AKI for individuals at high risk patients (Fig. 1).

Figure 1. Risk factors for chronic kidney disease following liver transplantation. MELD, model for end-stage liver disease.

Due to the scarcity of data concerning CKD management in LT recipients, it is imperative to prioritize strategies targeting CKD management, diabetes, and hypertension. LT recipients ought to undergo an annual evaluation of renal function alongside assessment for albuminuria. The CKD Epidemiology Collaboration and Modified Diet in Renal Disease equations have proven to be accurate in non-kidney solid organ transplant recipients and should thus be employed in LT recipients for kidney function assessment [11]. However, for individuals with lower muscle mass or body mass index, the CKD Epidemiology Collaboration cystatin C equation should be utilized as a confirmatory test [12-14]. Guidance from the Kidney Disease Improving Global Outcomes (KDIGO) clinical recommendations, pertinent to this demographic, can be applied and consolidated for reference, as outlined in Table 1 [15,16].

Table 1 . Recommendations from Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines for chronic kidney disease (CKD) and hypertension that are relevant to liver transplant recipients.

	Recommendation
Hypertension	Systolic blood pressure exceeding 140 mmHg: manage aiming for a target below 140 mmHg (Grade 1B).
	Urinary albumin excretion (UAE) ranging from 30 to 300 mg/day: consider Renin-Angiotensin System inhibitors (RASi) (Grade 2C).
	UAE equal to or greater than 300 mg/day: initiate treatment with RASi (Grade 1B).
	In cases of diabetes mellitus and UAE between 30 to 300 mg/day: commence therapy with RASi (Grade 1B).
Diabetes	Tailored HbA1c targets, varying from less than 6.5% to less than 8.0%, are recommended for patients with diabetes and CKD who are not undergoing dialysis (Grade 1C).
	For individuals with Type 2 diabetes, CKD, and an estimated glomerular filtration rate of 30 mL/min/1.73 m2 or higher, treatment with metformin is advised (Grade 1B).
Diet	Limit sodium intake to less than 2 g per day or less than 90 mmol per day (Grade 2C).
	Refrain from consuming excessive protein (>1.3 g/kg/day).
	For individuals with a glomerular filtration rate (GFR) below 30 mL/min/1.73 m2, maintain protein intake at 0.8 g/kg/day (Grade 2B).
Metabolic acidosis	Bicarbonate supplementation should be administered to ensure serum bicarbonate levels remain within the normal range for individuals with serum bicarbonate below 22 mmol/L (Grade 2B).
Lifestyle	Engage in physical activity that promotes cardiovascular health and is well-tolerated (striving for a minimum of 30 minutes, five times per week), maintain a healthy weight (with a body mass index between 20 and 25, adjusted according to country-specific demographics), and discontinue smoking (Grade 1D).
Nephrology referral	Acute kidney injury or a sudden sustained decline in GFR.
	GFR below 30 mL/min/1.73 m2.
	Consistent and significant albuminuria (urinary albumin-to-creatinine ratio ≥300 mg/g or albumin excretion rate ≥300 mg/day, equivalent to urinary protein-to-creatinine ratio ≥500 mg/g or protein excretion ≥500 mg/day).
	Progression of CKD.
	Presence of urinary red cell casts or more than 20 red blood cells per high-power field, which is sustained and not easily explained.
	CKD combined with hypertension resistant to treatment with four or more antihypertensive agents.
	Persistent abnormalities in serum potassium levels.
	Recurrent or extensive nephrolithiasis.
	Hereditary kidney disease.

For patients with CKD, blood pressure targets should aim for less than or equal to 140/90 mmHg if there’s no proteinuria, and <130/80 mmHg if proteinuria or diabetes is present. Calcium channel blockers are suggested as the primary treatment for hypertension in LT recipients, as they may counteract CNI-induced vasoconstriction [17]. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are also considered safe and effective post-transplant, especially for patients with proteinuria. Sodium/glucose cotransporter 2 inhibitors are recommended as the initial therapy for diabetes in CKD patients, as they can slow CKD progression in both diabetic and nondiabetic individuals [18,19]. However, their usage in non-kidney solid organ transplant recipients requires further investigation due to potential infection and metabolic risks, necessitating careful monitoring.

The current KDIGO guideline emphasizes timely referral to a nephrologist for access creation, considering the anticipated time to dialysis [20]. This decision is informed by kidney risk failure equations and the clinical judgment of nephrologists. For kidney transplant recipients with declining allograft function, referral for access evaluation is recommended when GFR falls between 20 and 30 mL/min per 1.73 m², a guideline that can also apply to LT recipients. Early referral offers opportunities for patients to explore dialysis access options, such as hemodialysis versus peritoneal dialysis, as well as kidney transplant evaluation. Mortality rates among LT recipients on chronic dialysis exceed those of matched non-transplant dialysis cohorts [21]. Several studies have shown a survival advantage of kidney transplantation over remaining on dialysis for non-kidney solid organ transplant recipients [22,23]. However, due to organ shortages and potential comorbidities, many LT recipients with CKD will require initiation of dialysis for kidney failure treatment. Hemodialysis is the predominant modality among LT recipients with kidney failure, possibly due to factors such as delayed nephrology referral, limited dialysis modality education, infection risk, and feasibility following prior abdominal surgery [21]. Nonetheless, studies have shown that peritoneal dialysis can be a viable option for LT recipients, highlighting the importance of patient education on available modalities [24].

The primary focus in preventing post-LT renal dysfunction involves optimizing immunosuppressive protocols, primarily by minimizing the utilization of CNIs. Additionally, it is crucial to address and manage metabolic disorders, which are known risk factors for CKD, as they can exacerbate the nephrotoxic effects induced by CNIs.

A significant contributor to AKI during the immediate post-LT phase is the dose-dependent renal arteriolar vasoconstriction induced by CNIs [25]. This vasoconstrictive effect can be mitigated or reversed by minimizing CNI exposure immediately following LT [26]. To achieve this, induction immunosuppression with T-cell depleting agents like anti-thymocyte globulin (ATG) or interleukin-2 receptor antagonist such as basiliximab allows for delayed CNI introduction and the use of lower CNI doses [25,26]. Studies have indicated that maintaining lower tacrolimus levels (6–10 ng/mL) shortly after LT is associated with reduced renal dysfunction at 1-year post-LT compared to standard tacrolimus levels (>10 ng/mL) [27]. Early initiation of mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) or antimetabolites like mycophenolate mofetil (MMF) or mycophenolic acid (MPA) also facilitates lower CNI doses during the immediate post-LT period [25,26]. Besides the acute vasoconstrictive effects of CNIs, many patients develop CNI-induced ischemic glomerular and tubular toxicity, which can progress to CKD [25,27]. Although rare, CNI use can lead to thrombotic microangiopathy, which carries a poor prognosis [25-27].

Various strategies aimed at protecting renal function have been explored and documented, as summarized in Table 2. These encompass (1) postponing the initiation of CNIs following induction therapy with ATG or interleukin-2 receptor antagonist; (2) lowering CNIs levels through the addition of MMF or mTOR inhibitors; (3) complete withdrawal from CNI through early conversion to mTOR inhibitors, optionally with MMF/MPA; and (4) utilization of sustained-release formulations of tacrolimus to mitigate peak concentrations and potential CNI-associated toxicity.

Table 2 . Maximizing the utilization of immunosuppressive treatment to mitigate renal dysfunction following liver transplantation.

	Recommendation
Induction therapy (basiliximab)	Consideration should be given to basiliximab induction in patients exhibiting baseline renal impairment or those at a high anticipated risk of renal dysfunction immediately after transplantation.
	Basiliximab induction may also be contemplated for all liver transplant recipients, regardless of their renal function status.
	Basiliximab induction facilitates the postponement of tacrolimus initiation.
	Basiliximab induction facilitates the maintenance of lower tacrolimus levels during the immediate post-transplant period.
Calcineurin inhibitor (tacrolimus)	Avoiding excessive tacrolimus exposure (>10 ng/mL) during the initial post-liver transplant phase.
	Delaying the initiation of tacrolimus until day 4 following transplantation.
	Maintaining tacrolimus trough levels at a lower range (5–7 ng/mL) during the first three months.
	Adjusting tacrolimus trough levels to an even lower range (3–5 ng/mL) after the initial three months.
	Considering tacrolimus discontinuation after the first year in patients experiencing ongoing renal dysfunction.
	For patients continuing tacrolimus therapy, minimizing levels after the initial 3–6 months while closely monitoring liver allograft function.
	Exploring the use of once-daily delayed-release tacrolimus formulations in all patients.
Mycophenolate	Initiating mycophenolate within the first two weeks enables the lowering of tacrolimus doses.
	There’s an elevated risk of rejection when mycophenolate is employed as the sole immunosuppressive agent.
	In cases where mTOR inhibitors are inaccessible or not well-tolerated, the utilization of mycophenolate may serve as an alternative for minimizing tacrolimus exposure.
mTOR inhibitor (everolimus)	Incorporating everolimus into a tacrolimus-based immunosuppressive regimen facilitates the reduction of tacrolimus dosage.
	Contemplate initiating everolimus early (<4 weeks) in patients experiencing ongoing renal dysfunction post-transplant.
	Aim for everolimus levels between 5–8 ng/mL when planning to reduce tacrolimus trough levels to 3–5 ng/mL.
	Consider early initiation of everolimus (<3 months) in all patients with identified risk factors for renal dysfunction.
	Early initiation of everolimus may be warranted in all patients if there are no contraindications and the patient demonstrates good tolerability.

mTOR, mammalian target of rapamycin..

Administering high-dose corticosteroids, typically methylprednisolone, during the anhepatic phase is standard procedure [28]. However, even with high-dose steroids, it’s crucial to initiate CNI on the first or second postoperative day to prevent early rejection [28]. The high dose and early use of CNIs are nephrotoxic, prompting the development of regimens aimed at delaying their introduction. One proposed method involves initiating induction immunosuppression therapy with ATG or interleukin-2 receptor antagonist and introducing CNIs after the first 3 to 5 days [13,29,30]. This approach circumvents the synergistic vasoconstrictive effects of CNIs when combined with known perioperative risk factors for AKI. Multiple clinical trials have demonstrated that induction therapy with ATG or interleukin-2 receptor antagonist followed by delayed CNI introduction at a lower dose yields superior renal outcomes in individuals with preoperative renal dysfunction [31-34]. While ATG is less frequently used in LT due to its adverse effects such as prolonged lymphopenia and infection risk [35], studies have shown that interleukin-2 receptor antagonist induction, particularly with basiliximab, offers similar efficacy with fewer side effects compared to ATG [35-37]. Basiliximab induction followed by delayed CNI introduction has been found beneficial for renal function without increasing short-term rejection rates (<12 months) or other complications [33,36,38,39]. Interleukin-2 receptor antagonist induction also eliminates the need for corticosteroids, enabling steroid-free immunosuppression and consequently reducing the risk of opportunistic infections and metabolic complications. In practice, basiliximab 20 mg is intravenously administered on postoperative days 0 and 4, with tacrolimus withheld until postoperative day 5. Another induction regimen involving the co-stimulation blockade agent belatacept was discontinued due to higher rates of acute rejection and unexplained mortality in the belatacept group [40].

Given the inherent nephrotoxicity of CNI, it’s logical to pursue strategies aimed at reducing CNI levels or completely discontinuing them to preserve or enhance renal function in post-LT patients [41]. At present, alternative immunosuppressive agents include mTOR inhibitors and MMF and MPA. However, relying solely on monotherapy with either mTOR inhibitors or antimetabolites, while beneficial for renal function, poses a high risk of rejection and thus isn’t recommended [41].

In a multicenter prospective study that randomized de novo LT patients to standard tacrolimus or reduced tacrolimus with MMF, the reduced tacrolimus group exhibited higher one-year estimated glomerular filtration rate (eGFR) along with a reduced risk of acute rejection [42]. Concerning mTOR inhibitors, the use of sirolimus isn’t advised in the immediate postoperative period (<1 month) due to its association with increased risks such as hepatic artery thrombosis, impaired wound healing, graft loss, sepsis, and excess mortality [43]. However, studies evaluating sirolimus beyond the initial month post-LT have shown renal protective benefits [44].

In the multicenter Spare the Nephron Liver trial, the sirolimus with MMF group demonstrated superior renal function improvement compared to the CNI with MMF group, although rates of acute rejection and discontinuation due to adverse events were higher in the sirolimus arm [44]. Conversely, early initiation of everolimus with tacrolimus has been proven safe and offers renal protective advantages. In studies where everolimus was introduced 4 weeks after LT, adverse events such as hepatic artery thrombosis and impaired wound healing were notably absent [44-49]. Additionally, everolimus boasts a considerably shorter half-life than sirolimus, facilitating easier dose adjustments and drug level monitoring [41]. Consequently, many transplant centers now favor everolimus over sirolimus in renal protective protocols.

Although mTOR inhibitors offer nephroprotection, both sirolimus and everolimus can induce proteinuria and exacerbate pre-existing renal dysfunction. The precise mechanism by which mTOR inhibitors impact glomerular permeability and provoke proteinuria remains unclear, but the reduction in vascular endothelial growth factor synthesis and expression is thought to be a contributing factor, leading to compromised podocyte structural integrity [50,51].

Transitioning from CNI to mTOR inhibitor therapy should be approached cautiously in patients presenting with existing proteinuria (>800 mg/day) or an eGFR <40 mL/min [41,52]. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may be beneficial in managing mild proteinuria. However, if proteinuria worsens, discontinuation of the mTOR inhibitor may be necessary to mitigate the risk of renal failure. Typically, proteinuria resolves within several months following mTOR inhibitor discontinuation, with most patients exhibiting no long-term residual kidney damage [53].

Early initiation of mTOR inhibitor therapy is crucial for improving renal function in patients with CNI-induced nephropathy [45-49]. Studies have demonstrated that patients receiving everolimus within 30±5 days or even earlier (≤10 days) post-LT show significant improvement in eGFR of 8–12 mL/min/1.73 m² at 12 months after transplantation [47-49]. Notably, the pivotal phase-3 H2304 trial revealed that renal function was significantly enhanced up to 36 months in patients receiving everolimus alongside reduced tacrolimus compared to those on standard tacrolimus, with comparable rejection rates [46]. The HEPHAISTOS trial further supported this, showing a numerically higher eGFR in patients receiving early everolimus introduction along with reduced-dose tacrolimus [54]. Similarly, the EPOCAL study demonstrated significantly higher eGFR in patients receiving very early everolimus introduction, as early as 2 weeks after randomization [55]. Additionally, the PROTECT study explored the feasibility of de novo everolimus use without CNI therapy post-transplantation, revealing notable improvements in eGFR over time [49]. The adjusted mean eGFR benefit at 3 years favored an everolimus-based tacrolimus-free regimen, with similar rates of acute rejection, graft loss, and mortality between the two groups [47].

Once renal function declines significantly (GFR <60 mL/min/1.73 m²), attempts to lower tacrolimus levels and introduce everolimus or MMF/MPA may be less effective in improving GFR, possibly due to irreversible renal structural damage. In fact, initiating mTOR inhibitors after renal dysfunction sets in may exacerbate existing renal disease and induce proteinuria. Late conversion to MMF monotherapy or combined with low-dose CNI has shown limited efficacy in increasing GFR. A recent systematic review examining complete CNI withdrawal in favor of MMF for renal dysfunction found that GFR improved by an average of 8.3 mL/min when MMF was used alongside CNI reduction or elimination, even in cases with GFR <30 mL/min.

The Everolimus Liver Registry (EVEROLIVER) is an observational database spanning nine centers in France, documenting all LT recipients prescribed everolimus [56]. Over a five-year period, real-life data from this registry revealed that CNI withdrawal was achievable in 57.7% of patients by month 60. Remarkably, even individuals with pre-existing CKD at baseline demonstrated enhanced eGFR at both 36 and 60 months.

Notably, early conversion to everolimus (<3 months) was linked to a higher likelihood of eGFR improvement compared to late conversion (55% vs 39.4%) in CKD patients. However, the utilization of everolimus is hindered by side effects, limiting its use in approximately 20% of cases, including cytopenia, aphthous ulcers, edema, proteinuria, and dyslipidemia. Similarly, complete cessation of CNI in favor of everolimus alone poses an elevated risk of early rejection unless supplemented with MMF/MPA [56].

Once renal function declines significantly (GFR <60 mL/min/1.73 m²), attempts to lower tacrolimus levels and introduce everolimus or MMF/MPA may be less effective in improving GFR, possibly due to irreversible renal structural damage [41,57]. In fact, initiating mTOR inhibitors after renal dysfunction sets in may exacerbate existing renal disease and induce proteinuria [57]. Late conversion to MMF monotherapy or combined with low-dose CNI has shown limited efficacy in increasing GFR [58]. A recent systematic review examining complete CNI withdrawal in favor of MMF for renal dysfunction found that GFR improved by an average of 8.3 mL/min when MMF was used alongside CNI reduction or elimination, even in cases with GFR <30 mL/min [59].

CKD post-LT is common with associated adverse outcomes, stemming from various risk factors. Early identification and modification are crucial. Utilizing KDIGO recommendations for CKD and hypertension management is reasonable. Adjusting the immunosuppressive regimen, particularly by minimizing CNIs in the first post-transplant year, can slow kidney dysfunction progression. Identifying and addressing risk factors for renal dysfunction, optimizing perioperative care, and tailoring immunosuppressive regimens are essential steps to enhance long-term outcomes following LT.

There was no funding related to this study.

All authors have no conflicts of interest to declare.