Rethinking chronic kidney disease risk after liver transplantation

Abstract

In this editorial, we comment on the article by Muñoz-Serrano et al published in the World Journal of Transplantation. Chronic kidney disease (CKD) is one of the most frequent and severe complications after liver transplantation (LT), threatening long-term survival beyond graft-related issues. Its pathogenesis is multifactorial, combining calcineurin inhibitor (CNI) nephrotoxicity with pre- and perioperative renal insults and metabolic comorbidities. We reviewed recent evidence from clinical trials, meta-analyses, and practice guidelines evaluating risk factors and management of CKD after LT, with a focus on immunosuppression strategies, perioperative care, and prognostic determinants. CKD develops in approximately 30% of LT recipients at 1 year and exceeds 40% at 5 years, with stage G3 predominating. Key predictors of post-LT CKD include high pre-LT creatinine [odds ratio (OR) = 7.74], early post-LT acute kidney injury (OR = 2.72), hypertension (OR = 4.833), and metabolic dysfunction-associated steatotic liver disease, including non-alcoholic steatohepatitis, as the underlying etiology. Tacrolimus remains superior to cyclosporine in overall survival and hypertension control, though hypomagnesemia and diabetogenicity are clinically relevant toxicities. CNI minimization - through basiliximab induction, low-dose tacrolimus with mycophenolate, or everolimus conversion - improves renal outcomes without compromising graft survival, despite trade-offs such as mild acute rejection or higher malignancy rates. CKD at 1 year confers a 4.48-fold increase in mortality risk, underscoring the prognostic weight of renal preservation. Renal protection after LT requires systematic preoperative risk stratification, perioperative CNI minimization, individualized immunosuppression, and aggressive metabolic management. Future integration of non-invasive biomarkers, including kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, together with standardized simultaneous liver-kidney transplantation criteria, may further refine patient-tailored nephroprotection strategies. Muñoz-Serrano et al retrospectively analyzed 594 liver transplant recipients over three decades to identify risk factors for CKD at one year post-transplant. The authors identified older age, female sex, pre-transplant renal dysfunction, and treatment with cyclosporine A as independent risk factors.

Key Words: Liver transplantation; Chronic kidney disease; Calcineurin inhibitors; Tacrolimus; Immunosuppression; Acute kidney injury; Renal protection

Core Tip: Chronic kidney disease following liver transplantation is a critical, modifiable determinant of long-term survival. Its pathogenesis extends beyond calcineurin inhibitor (CNI) toxicity to include pre-transplant renal dysfunction, perioperative acute kidney injury, and metabolic comorbidities like hypertension. Consequently, shifting focus toward early nephroprotection is essential. Evidence supports a multi-pronged approach: proactive perioperative hemodynamic management, the use of basiliximab induction to safely delay CNI exposure, mycophenolate-based CNI minimization, and aggressive metabolic control. These strategies significantly enhance long-term renal preservation without compromising graft integrity.

This editorial refers to “Chronic kidney disease at one year after liver transplantation: Role of changes in immunosuppression over three decades” by Muñoz-Serrano et al, 2025; https://dx.doi.org/10.5500/wjt.v15.i4.108791

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INTRODUCTION

In a recent issue of World Journal of Transplantation, Muñoz-Serrano et al[1] published a comprehensive retrospective analysis examining the evolution of renal function in the first year after liver transplantation across three decades. Their study, which included 594 adult recipients transplanted between 1987 and 2019, provides valuable insights into how changes in immunosuppressive protocols have impacted the incidence of chronic kidney disease (CKD). The authors found that 48.8% of patients developed CKD at one year post-transplant, with older age [odds ratio (OR) = 1.03)], female sex (OR = 1.88), pre-transplant renal dysfunction (OR = 2.69), and treatment with cyclosporine A (OR = 3.77) emerging as independent risk factors. Importantly, among patients treated with tacrolimus, the addition of mycophenolic acid was associated with a lower incidence of renal dysfunction (OR = 1.85), while basiliximab induction significantly reduced acute kidney injury at one month. These findings prompt a re-evaluation of our approach to renal protection in liver transplant recipients. CKD represents one of the most critical challenges threatening the long-term survival of liver transplantation (LT) recipients, second only to graft-related complications. As demonstrated by Muñoz-Serrano et al[1], the development of renal dysfunction remains a frequent and complex complication that demands a re-evaluation of our management strategies. Post-LT CKD is clinically defined as a persistent decline in estimated glomerular filtration rate (eGFR) below 60 mL/minute/1.73 m²[2]. Its etiology is multifactorial, resulting from an interplay of pre-existing renal vulnerability, perioperative insults, and chronic exposure to nephrotoxic immunosuppressive agents, predominantly the calcineurin inhibitors (CNIs)[2]. The incidence of post-LT CKD is substantial and increases markedly over time. CKD is diagnosed in approximately 30% of recipients at one year post-transplant, rising to 42.9% at five years[3]. Most cases are classified as stage G3, accounting for the majority of diagnoses at the five-year follow-up, highlighting a significant moderate-level burden on renal function[3]. Development of CKD post-LT is not merely a comorbidity; it is a major determinant of long-term mortality. Patients with CKD at one year post-LT have a 4.48-fold higher risk of death compared with those maintaining normal renal function. This establishes the first post-LT year as a critical prognostic period, emphasizing the need for careful renal preservation through optimized perioperative management and tailored immunosuppression[4].

THE NON-IMMUNOSUPPRESSIVE DETERMINANTS OF RENAL DYSFUNCTION: RISK STRATIFICATION

Identifying and managing non-immunosuppressive risk factors is essential to improve long-term renal outcomes. These intrinsic and acquired vulnerabilities establish the patient’s baseline susceptibility to the unavoidable nephrotoxic effects of CNI therapy, necessitating a stratified approach to care. The patient’s renal status immediately preceding and following the transplant procedure dictates long-term nephrological outcomes. Preoperative GFR and pre-LT serum creatinine[3] are powerful, independent predictors of new-onset CKD. Specifically, a high pre-LT serum creatinine level demonstrated (OR = 7.74, 95% confidence interval: 1.99-30.02) for predicting subsequent CKD development[5].

Furthermore, acute kidney injury (AKI) in the immediate perioperative period is a major accelerant of chronic disease. AKI affects more than 50% of LT recipients within the first seven days post-LT[3]. This early AKI status is identified as an independent predictor of CKD development at five years post-LT (OR = 2.72, 95% confidence interval: 1.22-6.06). The pathway from AKI to CKD progression is driven by incomplete tubular repair and residual cellular injury. This process is significantly exacerbated by the immediate introduction of high-dose CNIs after transplantation. Therefore, optimized perioperative management focused on hemodynamic stability and renal monitoring is crucial to minimize the progression from acute insult to irreversible end-stage kidney disease[3].

The patient’s overall metabolic and cardiovascular health post-LT strongly modulates renal prognosis. Hypertension and diabetes mellitus are recognized globally as major, modifiable risk factors for generalized CKD progression. In the post-LT cohort, hypertension specifically emerged as an independent risk factor for new-onset CKD[6], with a high associated odds ratio (OR = 4.833)[5]. The underlying cause of cirrhosis is an important factor in assessing pre-existing renal vulnerability. Liver disease due to non-alcoholic fatty liver disease or non-alcoholic steatohepatitis (NASH), now more broadly referred to as metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis, is closely associated with metabolic syndrome, which encompasses obesity, hypertension, hyperglycemia, and hyperlipidemia[7,8]. Patients undergoing LT for NASH/MASLD effectively present a “dual hit” scenario. They possess a pre-existing state of chronic inflammation, endothelial dysfunction, and metabolic distress. When this inherent vulnerability is compounded by the systemic vascular constrictive effects of CNIs, their risk of developing severe, rapid CKD may be higher compared to patients with non-metabolic etiologies, suggesting the need for careful risk management[7,8].

DEMOGRAPHIC PREDICTORS (AGE AND SEX)

Age is universally recognized as the most important non-modifiable risk factor for CKD[6]. The role of sex, however, is complex and often dependent on age and the accumulation of metabolic comorbidities. While some studies in the general population suggest that male sex may be a risk factor for CKD progression[9], other data indicate that women aged 60 and older have a higher prevalence of advanced diabetic kidney disease[10], hypertension, and obesity compared to men of the same age group. Therefore, the risk is not determined solely by sex, but is more likely influenced by the accumulation and expression of metabolic comorbidities, such as obesity, hypertension, and diabetes mellitus, within specific age and sex subgroups after LT. This highlights the need for careful monitoring of all older recipients, regardless of sex[9]. The key non-immunosuppressive determinants are summarized below, in Table 1, emphasizing the need for comprehensive pre- and peri-transplant risk assessment.

Table 1 Summary of key non-immunosuppressive chronic kidney disease risk factors post-liver transplantation.

Ref.	Risk factor category	Specific predictor	Clinical significance
Muñoz-Serrano et al[1], 2025	Demographics	Female sex	Independent risk factor for CKD at 1 year (OR = 1.88)
Li et al[5], 2018	Pre-transplant status	High pre-LT serum creatinine/Low GFR	Strongest independent predictor of long-term CKD (OR = 7.74 for Cr)
Li et al[5], 2018	Perioperative event	AKI within 7 days post-LT	Major independent determinant of CKD progression (OR = 2.72)
Li et al[5], 2018	Metabolic comorbidity	Hypertension (post-LT)	Powerful independent risk factor for new-onset CKD (OR = 4.833)
Canbay et al[7], 2016	Etiology/comorbidity	NAFLD/NASH cirrhosis	Pre-existing inflammatory/metabolic burden elevates inherent CKD risk
Mallamaci et al[6], 2024	Demographics	Older age	Non-modifiable primary risk factor for CKD

AKI: Acute kidney injury; CKD: Chronic kidney disease; Cr: Creatinine; GFR: Glomerular filtration rate; LT: Liver transplantation; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; OR: Odds ratio.

COMPARATIVE NEPHROTOXICOLOGY OF CNIS

Tacrolimus (TAC) and cyclosporine (CsA) are the primary immunosuppressive agents used after LT[11]. Both drugs inhibit interleukin-2 messenger RNA transcription and share similar mechanisms of renal toxicity, primarily causing chronic vascular injury (such as renal vasospasm) and direct tubular toxicity (including epithelial cell vacuolization). Because both agents act through these fundamental molecular and hemodynamic pathways, differences in long-term CKD incidence are mainly due to variations in systemic side effects or the required therapeutic drug levels, rather than differences in their intrinsic nephrotoxicity[11].

TAC vs CsA: Comparative efficacy and nephrotoxic profiles

Meta-analyses of randomized controlled trials published since 2000 establish TAC as the cornerstone of immunosuppressive therapy post-LT[12]. TAC has generally been shown to be superior to CsA in reducing patient mortality and providing better control of hypertension, while rates of graft loss and acute rejection are typically equivalent between the two agents[11,12]. Although CsA is associated with a lower incidence of new-onset diabetes after transplantation compared to TAC[12], the overall renal profile of TAC is favored due to its lower association with systemic hypertension. Since post-LT hypertension is a strong, independent predictor of CKD progression, the benefit of TAC in reducing vascular risk factors likely contributes to superior long-term renal outcomes, despite its higher risk of diabetogenicity[5,11,12].

A more nuanced approach is required for certain subgroups, such as patients undergoing transplantation for hepatitis C virus infection. In this context, the incidence of graft loss has been reported to be significantly higher in patients treated with TAC compared to those receiving CsA (with a risk ratio of 0.52 for CsA relative to TAC)[12]. This finding suggests that CsA may be the preferred initial immunosuppressive agent in specific clinical situations, particularly when the risk of graft loss outweighs concerns about renal preservation[12]. While TAC remains the preferred first-line CNI for most patients, CsA may be considered in cases of intolerance or contraindications to TAC (such as severe neurotoxicity, tremor, or refractory diarrhea), in patients at high risk for new-onset diabetes after transplantation, or in rare cases of hepatitis C virus-positive recipients where CsA’s antiviral properties may be advantageous[12-14]. Thus, the choice between TAC and CsA should be individualized, balancing nephrotoxicity, metabolic effects, and overall survival, as summarized in Table 2.

Table 2 Comparative profile of tacrolimus vs cyclosporine A post-liver transplantation.

Ref.	Clinical outcome	TAC profile (relative to CsA)	CsA profile (relative to TAC)	Supporting evidence type
Muduma et al[12], 2016	Patient mortality	Superior/Lower risk	Higher risk	RCTs/meta-analysis
Muduma et al[12], 2016	New-onset diabetes (NODAT)	Higher risk	Superior/Lower risk	RCTs/meta-analysis
Randhawa et al[11], 1997; Muduma et al[12], 2016	Hypertension	Superior/Lower risk	Higher risk	RCTs/meta-analysis
Muduma et al[12], 2016	Graft loss (overall)	Equivalent	Equivalent	RCTs/meta-analysis
Muduma et al[12], 2016	Graft loss (HCV subgroup)	Higher risk	Superior/Lower risk	Meta-analysis

CsA: Cyclosporine A; HCV: Hepatitis C virus; LT: Liver transplantation; NODAT: New-onset diabetes after transplantation; RCTs: Randomized controlled trials; TAC: Tacrolimus.

CNI MINIMIZATION AND SPARING STRATEGIES FOR RENAL PROTECTION

Given the established dose-dependent nephrotoxicity of CNIs[5], minimization and avoidance strategies are essential therapeutic pillars for managing renal risk in LT recipients. These strategies aim to reduce CNI exposure while leveraging adjuvant agents to maintain adequate immunosuppressive efficacy and prevent rejection. Induction therapy using agents such as Basiliximab (an anti-interleukin-2R antibody) is employed to facilitate the safe delay of CNI introduction, a maneuver particularly critical for patients suffering from post-operative renal insufficiency[15]. Clinical studies have shown that Basiliximab-induced protocols are a safe regimen, achieving similar rates of patient survival and acute rejection compared to standard immunosuppression[16].

Crucially, this strategy demonstrated a significant reduction in medium-term renal dysfunction post-LT, with an incidence of 7.1% in the Basiliximab group compared to 19.1% in the control group[16]. The rationale for this benefit is that delaying CNI initiation mitigates exposure during the “critical window” of the immediate post-operative phase, when the native kidneys are maximally vulnerable due to ischemia/reperfusion injury, AKI recovery, and hemodynamic instability. Delayed CNI administration following Basiliximab induction in patients with post-operative renal insufficiency has been shown not to adversely affect the incidence of biopsy-proven acute rejection (BPAR) or long-term renal outcomes[15].

CNI SPARING THROUGH ADJUNCTIVE MAINTENANCE THERAPY

Mycophenolate mofetil

The addition of mycophenolate mofetil (MMF) is the most widely supported and proven CNI minimization strategy. A meta-analysis encompassing 32 trials, representing 1383 patients, demonstrated that CNI minimization protocols, most commonly achieved with the addition of MMF, led to significant improvements in kidney function. This improvement was realized without incurring differences in acute rejection episodes or compromising long-term patient survival[17]. In a clinical setting, conversion to MMF-TAC minimization therapy has been observed to significantly improve renal function, demonstrate good tolerability, and result in favorable five-year survival rates (75.3%). The success of this strategy supports the clinical hypothesis that chronic CNI nephrotoxicity is dose-dependent and that effective sparing, achieved via adjunct antiproliferative agents, may improve renal outcomes[18].

mTOR INHIBITORS (EVEROLIMUS)

The mammalian target of rapamycin (mTOR) inhibitors, such as everolimus (EVR), offer an alternative non-nephrotoxic mechanism for CNI avoidance or minimization. The 5-year follow-up data from the CERTITUDE observational study compared EVR-based regimens against TAC-based regimens. The overall long-term efficacy and safety were reported as comparable between the two regimens up to five years post-LT[19]. EVR-based regimens are most commonly used in combination with low-dose TAC, rather than with MMF. The rationale for combining EVR with TAC is to allow CNI minimization, thereby reducing nephrotoxicity while maintaining adequate immunosuppression. Conversely, EVR plus MMF without CNI has been studied, offering the advantage of further reducing CNI-related renal injury. However, this comes at the cost of increased risk of acute rejection and higher rates of adverse effects such as proteinuria, myelosuppression, and impaired wound healing. Consequently, these CNI-free regimens are generally reserved for patients with significant CNI toxicity or intolerance and require close monitoring[13,14,19,20]. Studies have also evaluated CNI-free regimens combining EVR with MMF. The main theoretical advantage of this strategy is the complete elimination of CNI-related nephrotoxicity, allowing maximal potential for renal recovery and improvements in estimated GFR compared with CNI-based regimens. However, these benefits are offset by clinically relevant drawbacks: CNI-free combinations are consistently associated with higher rates of (BPAR) and a distinct adverse-event profile, including increased proteinuria, dyslipidemia, stomatitis, and impaired wound healing. For these reasons, EVR + MMF without CNI is not considered a standard first-line option and is generally reserved for highly selected recipients with severe CNI intolerance or specific contraindications to CNI therapy[14,20]. A wide range of renal-sparing strategies, including basiliximab induction with delayed CNI introduction, reduced-dose TAC combined with MMF, and early conversion to mTOR inhibitors, have been tested with varying success. Their efficacy in preserving renal function post-LT is summarized in Table 3.

Table 3 Efficacy of calcineurin inhibitor minimization strategies on renal outcomes post-liver transplantation.

Ref.	Strategy	Primary mechanism of renal protection	Renal outcome	Trade-off/safety signal	Evidence source
Muñoz-Serrano et al[1], 2025; Kong et al[17], 2011	MMF addition/conversion	Reduces the required CNI trough level	Significant long-term eGFR improvement	Low rejection rate; generally well tolerated	Retrospective study Meta-analysis/conversion studies
Lange et al[15], 2018; Hashim et al[16], 2020	Basiliximab induction	Enables delayed CNI initiation	Reduces medium-term renal dysfunction post-LT (7.1% incidence)	Does not adversely affect BPAR or survival	Clinical trial/review
Saliba et al[19], 2022	EVR avoidance	Non-nephrotoxic primary mechanism	Renal function potentially better preserved in actual treatment subgroups	Higher BPAR; higher rate of de novo cancer observed	Observational/follow-up study

BPAR: Biopsy-proven acute rejection; LT: Liver transplantation; CNI: Calcineurin inhibitor; eGFR: Estimated glomerular filtration rate; EVR: Everolimus; MMF: Mycophenolate mofetil.

In addition to basiliximab, perioperative CNI minimization protocols may include induction with thymoglobulin (rabbit anti-human T-lymphocyte globulin). This strategy is primarily indicated for patients at high immunological risk or those with severe pre-existing renal dysfunction (e.g., requirement for pre-transplant dialysis). Thymoglobulin allows for a prolonged delay in CNI introduction, thereby shielding the kidney during the critical recovery phase. However, this benefit must be balanced against a higher risk of infectious complications and cytopenias compared to non-depleting agents[13,20,21]. Regarding renal function, while the mean absolute change in eGFR over five years was statistically similar between the TAC (15.53 mL/minute/1.73 m²) and EVR (14.56 mL/minute/1.73 m²) groups, renal function was observed to be better preserved in subgroups categorized by actual EVR treatment received[19].

However, the use of EVR involves crucial clinical trade-offs requiring careful risk stratification. Treated BPAR was significantly higher in the EVR group (15.4% for EVR vs 6.4% for TAC), although the majority of these events were mild. Furthermore, a significant safety signal involves malignancy: The incidence of de novo cancer was higher in the EVR group (14 patients vs 5 patients in the TAC group). Conversely, recurrence of hepatocellular carcinoma (HCC) was observed exclusively in the TAC group (n = 4)[19]. This suggests a potential oncologic protective benefit for EVR, consistent with its mechanism of action, which is particularly relevant in patients transplanted for HCC. Therefore, EVR minimization is strategically best deployed in patients where oncological surveillance is prioritized (e.g., following transplantation for HCC) or those with severe, established CNI-induced nephrotoxicity, balancing the increased risk of acute rejection against the dual benefits of potential renal sparing and cancer prevention. From a methodological standpoint, the overall quality of evidence comparing maintenance regimens remains limited, and most recommendations rely mainly on observational data and expert consensus[14,21].

PROGNOSTIC IMPACT AND CLINICAL MONITORING OF POST-LT CKD

As established, the development of CKD by the one-year post-LT mark represents a critical point of clinical divergence, carrying an extreme mortality hazard ratio of 4.48[4]. These finding mandates that the first year post-LT be managed as a crucial stabilization period. This window requires not only the tailored application of immunosuppression strategies but also aggressive management of co-morbidities, particularly hypertension and diabetes, which accelerate renal decline. The failure to stabilize eGFR during this time signifies a deeply concerning prognostic trajectory[4].

Monitoring CKD progression relies on calculating eGFR using validated formulas, such as the Chronic Kidney Disease Epidemiology Collaboration or the Modification of Diet in Renal Disease study equation[22,23]. Serum creatinine is an insensitive marker, particularly in sarcopenic or diabetic patients, where muscle mass variations can affect results. In these metabolic contexts, the integration of cystatin C-based equations has demonstrated enhanced accuracy in estimating GFR, offering a more reliable tool for early stratification. Additionally, serum creatinine typically only rises after a significant loss of kidney function has already occurred[23].

Consequently, there is growing interest in non-invasive biomarkers for early diagnosis and differentiation of renal injury. While current reports in the LT field are scarce, data extrapolated from kidney transplantation research indicate that urinary markers like kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin show promise[24]. These markers can potentially differentiate acute CNI nephrotoxicity from acute rejection, providing a non-invasive tool to guide therapeutic adjustments (e.g., rapid CNI dose reduction) before irreversible chronic damage occurs. Future guidelines for LT are expected to incorporate such biomarkers to provide more precise guidance than creatinine monitoring alone allows[24].

CURRENT GUIDELINES AND EXPERT CONSENSUS FOR RENAL PROTECTION

The American Association for the Study of Liver Diseases and the American Society of Transplantation have published comprehensive practice guidelines focusing on the diagnosis and management of graft-related complications in adult LT recipients[25]. These guidelines synthesize the latest evidence on key post-transplant issues, including graft rejection, recurrent disease, and immunosuppressive strategies[25]. The methodology employs a multidisciplinary expert writing group that rates the level of evidence using systems such as the Oxford Center for Evidence-Based Medicine[25]. The guideline explicitly addresses immunosuppression efficacy and safety, implicitly recognizing the imperative to minimize CNI-related organ damage. The guidelines acknowledge that while some aspects of graft management, such as immunosuppression efficacy, are supported by robust trial data, guidance on complex, long-term outcomes often relies on retrospective cohort data or extrapolation from other solid organ transplant fields. This framework underscores the transplant community’s commitment to optimizing long-term patient health, which includes prioritizing strategies to reduce nephrotoxic risk[25,26]. The European Association for the Study of the Liver released updated Clinical Practice Guidelines on Liver Transplantation in recent years, reflecting significant advancements in the field since 2016. These guidelines cover evolving indications and address the complexities of managing long-term patient health[27].

The updated guidelines place specific emphasis on re-evaluating immunosuppressive strategies based on their effects on long-term outcomes[27]. Crucially, the guidelines include updated assessment protocols for simultaneous liver-kidney transplantation (SLKT). The explicit focus on SLKT criteria signifies the growing clinical and consensus-driven recognition that advanced CKD status, both pre- and post-transplant, requires formalized, evidence-based management pathways, affirming the central role of renal preservation in the overall strategic management of LT patients[27].

While Kidney Disease: Improving Global Outcomes (KDIGO) does not produce specific guidelines dedicated solely to post-LT CKD management, the general KDIGO framework remains universally applicable for the nomenclature, diagnosis, prognosis, and management of CKD. The KDIGO staging system (G1-G5, based on GFR, and A1-A3, based on albuminuria) is essential for risk stratification and clinical prognostication in LT recipients, providing the standardized criteria used to identify the high-risk CKD stage G3 threshold noted at the one-year post-LT mark[3,28].

SYNTHESIS OF EVIDENCE-BASED NEPHROPROTECTION STRATEGIES

The comprehensive analysis of evidence published between 2015 and 2025 affirms that CKD is a major, often preventable, cause of morbidity and mortality following LT. Effective renal protection hinges on a multi-pronged approach that integrates rigorous risk stratification with strategic, evidence-based immunosuppression. CKD after LT is not an unavoidable byproduct of CNI therapy, but a modifiable determinant of survival.

Mandatory risk stratification

High-risk patients must be identified preoperatively. Key indicators include high pre-LT serum creatinine (OR = 7.74), a history of AKI within seven days post-LT (OR = 2.72), an underlying cirrhosis etiology linked to metabolic syndrome (NASH/MASLD), and uncontrolled post-LT hypertension (OR = 4.833)[3,5,7].

Perioperative CNI minimization

In high-risk patients, the use of basiliximab induction is strongly supported as it enables the delayed initiation of CNIs[15]. This strategy is not just safe, it is strongly recommended if we aim to protect the kidney during the most vulnerable post-operative window. This strategy effectively shields the kidneys during the critical post-operative period when they are most susceptible to injury, significantly reducing medium-term renal dysfunction rates (from 19.1% to 7.1%)[16].

Optimization of maintenance therapy

TAC is generally the preferred CNI agent over CsA due to its superior profile in reducing patient mortality and, critically, lowering the incidence of systemic hypertension, thereby mitigating a major non-immunosuppressive CKD risk factor[4,6,12]. For patients developing established CNI nephrotoxicity, conversion to or addition of MMF is the most consistently proven strategy for long-term renal function improvement[17,18]. Regarding mTOR inhibitors, EVR is specifically indicated for CNI minimization in recipients with CKD or a history of malignancy (particularly HCC). From a practical standpoint, it should be used in association with low-dose TAC to balance renal protection with efficacy. Conversely, CNI-free regimens (EVR without TAC) should generally be avoided in the early post-operative period due to rejection risks and reserved only for patients with severe CNI intolerance or specific contraindications[19]. A practical clinical algorithm summarizing these maintenance strategies based on patient risk profiles is provided in Table 4.

Table 4 Practical algorithm for maintenance immunosuppression after liver transplantation.

Step	Patient factors/clinical scenario	Preferred regimen	Alternative regimen/key considerations
1	Standard risk (normal renal function, no specific comorbidities)	TAC + MMF ± steroids	CsA + MMF ± steroids: Monitor closely for CNI toxicity and NODAT
2	Renal dysfunction (eGFR < 60 mL/minute) or CNI toxicity	EVR + low-dose TAC	Everolimus + MMF (CNI-free): Reserved for patients with severe CNI intolerance due to higher rejection risk; monitor for proteinuria and wound healing
3	History of malignancy (e.g., HCC history, skin cancer)	Everolimus-based regimen	Sirolimus-based regimen: Leverage the antineoplastic effects of mTOR inhibitors to reduce recurrence risk
4	High immunological risk (e.g., autoimmune etiology, young age)	Induction with thymoglobulin followed by TAC + MMF	Standard triple therapy: Consider delayed CNI introduction to protect renal function during the perioperative phase
5	SLKT recipients (Simultaneous liver-kidney transplant)	Standard CNI-based regimen	Individualized approach: Therapy must be tailored to protect the kidney graft while preventing liver rejection

Recommendations adapted from Nedredal et al[20] and Pollok et al[21]. TAC: Tacrolimus; MMF: Mycophenolate mofetil; CsA: Cyclosporine A; CNI: Calcineurin inhibitor; NODAT: New-onset diabetes after transplantation; EVR: Everolimus; HCC: Hepatocellular carcinoma; SLKT: Simultaneous liver-kidney transplantation.

Targeted clinical monitoring

The first year post-LT is paramount, as CKD diagnosis at this point carries a 4.48 times greater mortality risk[4]. Aggressive management of hypertension and diabetes mellitus is essential, coupled with high-frequency monitoring of eGFR[29]. Furthermore, emerging evidence highlights that optimal tacrolimus trough levels and intrapatient variability play a critical role in determining long-term renal outcomes[30]. In this context, the extensive retrospective analysis by Muñoz-Serrano et al[1], published in this issue, provides compelling evidence reinforcing the necessity of vigilant monitoring and tailored immunosuppression. Analyzing a cohort of 594 liver transplant recipients over three decades, the authors demonstrated that CKD at one year remains a frequent complication, affecting 48.8% of patients, and is significantly associated with reduced 5-year survival. These findings are further supported by randomized trial evidence demonstrating that reduced-dose tacrolimus with mycophenolate mofetil effectively preserves renal function without compromising graft survival[31]. Crucially, their multivariable analysis confirmed older age, female sex, and pre-existing renal dysfunction as independent predictors of post-transplant CKD, aligning with the risk stratification importance discussed herein. The study highlights the protective evolution of immunosuppressive strategies: While calcineurin inhibitors remain a double-edged sword, the transition to tacrolimus-based regimens, particularly when combined with mycophenolic acid (MPA), was associated with a marked reduction in renal dysfunction incidence. Notably, while basiliximab induction significantly mitigated acute kidney injury in the first month by allowing reduced early tacrolimus exposure, the authors observed that long-term renal preservation at one year was most strongly driven by the maintenance combination with MPA. These findings validate the shift towards minimization protocols and underscore that minimizing early acute injury must be paired with continuous maintenance optimization to effectively prevent chronic progression[1].

CONCLUSION

Further research is required to fully optimize renal protection. First, there is a substantial need for prospective, standardized clinical trials focusing specifically on the high-risk NASH/MASLD patient population to define the optimal CNI minimization protocols that address both their metabolic burden and their immunosuppressive requirements[7]. Second, the integration of non-invasive, objective biomarkers (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin) into routine clinical practice is necessary to enable personalized CNI dosing adjustments and identify acute nephrotoxicity before creatinine elevation signals irreversible chronic injury[24]. Finally, consensus on criteria and timing for SLKT, driven by recent advancements acknowledged in the European Association for the Study of the Liver guidelines, must be formalized to address the growing cohort of patients presenting with advanced pre-transplant kidney failure[27]. The evidence suggests that long-term transplant success is co-dependent on both graft and renal health[27]. Integrating nephroprotection into core management strategies is therefore essential to mitigating preventable mortality. Despite advances, key questions remain: The optimal timing for CNI minimization in MASLD recipients, the validation of urinary biomarkers in routine LT care, and standardized criteria for SLKT. Addressing these through prospective, tailored trials is essential to refining personalized nephroprotective approaches.