Objectives: Liver transplant markedly improves survival and quality of life in patients with chronic liver disease; however, chronic kidney disease remains a frequent long-term complication that adversely affects outcomes. In this study, we evaluated the effects of preoperative, perioperative, and postoperative factors on long-term renal outcomes, including chronic kidney disease and end-stage renal disease, as well as patient survival after liver transplant.
Materials and Methods: We conducted a retrospective, single-center cohort study of adult liver transplant recipients with 10-year follow-up. Renal function was assessed using serum creatinine levels and estimated glomerular filtration rate, and chronic kidney disease was defined as estimated glomerular filtration rate of <60 mL/min/1.73 m² persisting for at least 3 months. We analyzed clinical, perioperative, and postoperative variables to identify predictors of chronic kidney disease, end-stage renal disease, and 10-year mortality.
Results: Postoperative chronic kidney disease developed in 24% of recipients, with 6.7% progressing to end-stage renal disease. Advanced age, recurrent postoperative acute kidney injury, hepatitis B virus infection, alcohol use, cyclosporine-based immunosuppression, nephrotoxic antibiotics, and postoperative hypertension were independent predictors of chronic kidney disease, whereas hypertension and intensive nephrotoxic antibiotic exposure predicted progression to end-stage renal disease. Graft rejection rates were lower in patients with chronic kidney disease or end-stage renal disease (P < .⁰⁵). Hepatitis C virus positivity, hepatocellular carcinoma, and frequent postoperative infections predicted mortality, whereas renal dysfunction was not independently associated with 10-year survival.
Conclusions: Long-term renal dysfunction remains a major source of morbidity after liver transplant. Identification of high-risk patients, minimization of nephrotoxic exposures, optimization of blood pressure control, and renal-protective immunosuppressive strategies may help preserve kidney function. The lower rejection rates observed in patients with chronic kidney disease suggest a complex interaction between immune modulation and renal injury.

Key words : Acute kidney injury, Chronic kidney disease, Immunosuppression, Liver transplantation, Mortality

Introduction
Chronic liver disease accounts for nearly 2 million deaths annually, representing approximately 4% of all deaths worldwide, largely due to complications of cirrhosis and hepatocellular carcinoma.¹ Liver transplantation has substantially improved quality of life and long-term survival in patients with end-stage liver disease. As posttransplant survival has improved, late complications have become increasingly prominent. Among these, chronic kidney disease (CKD) is one of the most frequent and clinically significant comorbidities after transplant. The reported incidence of CKD after liver transplant varies widely, ranging from 20% to 50%, largely depending on definitions, estimated glomerular filtration rate (eGFR) calculations, and duration of follow-up.^2-4 A recent meta-analysis reported a 5-year cumulative incidence of stage 3 to 5 CKD of approximately 43%, highlighting the substantial burden of posttransplant renal dysfunction.⁵ Development and progression of CKD are associated with increased morbidity and mortality, impaired quality of life, higher health care costs, and reduced graft and patient survival.^6-8 Established risk factors for posttransplant CKD include preoperative factors, such as advanced age, preexisting renal dysfunction, high Model for End-Stage Disease (MELD) score, diabetes mellitus, hypertension, and hepatitis C infection, and perioperative and postoperative factors such as hemodynamic instability, ischemia-reperfusion injury, infections, exposure to nephrotoxic agents, early postoperative acute kidney injury (AKI), postoperative hypertension, and calcineurin inhibitor-based immunosuppression.^3,6,9-11 Although several studies have examined CKD after liver transplant, data on the long-term trajectory of renal function and its association with 10-year mortality remain limited, with many studies constrained by short follow-up durations and small sample sizes. To address this gap, we evaluated adult patients who underwent liver transplant for chronic liver failure at a single tertiary center over a 25-year period, with follow-up extending up to 10 years. We aimed to assess determinants of long-term renal outcomes (CKD and end-stage renal disease [ESRD]) and to examine their association with survival, as well as independent risk factors for mortality after liver transplant.

Materials and Methods
This study was conducted in accordance with the Declaration of Helsinki and approved by the Başkent University Medical and Health Sciences Research Board (Project No. KA23/237; July 25, 2023). The requirement for informed consent was waived due to the retrospective design. In this retrospective cohort study, we evaluated adult patients (≥18 years) who underwent liver transplant for chronic liver disease between April 1998 and April 2023 at Baskent University Ankara Hospital. We excluded patients with ESRD at the time of transplant or with less than 1 year of posttransplant follow-up. We obtained demographic characteristics, comorbidities, alcohol use, liver disease etiology, and cirrhosis-related complications. Transplant-related variables included donor type (living or deceased), retransplant status, and cold ischemia time. Posttransplant variables included the total number of AKI episodes, infection-related AKI, number of infectious episodes, exposure to nephrotoxic antibiotics and iodinated or gadolinium-based contrast agents, and immunosuppressive regimens. The development of postoperative conditions, such as diabetes mellitus, hypertension, atherosclerotic cardiovascular disease, malignancy (type), and graft rejection (type and time to rejection), was also documented. Renal function was assessed with serum creatinine levels and eGFR. Measurements were obtained at regular intervals during the first postoperative year and annually thereafter for up to 10 years after transplant. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.¹² Acute kidney injury and CKD were defined according to the Kidney Disease: Improving Global Outcomes 2012 criteria.^13,14 Acute kidney injury was defined based on changes in serum creatinine and/or urine output, with early postoperative AKI referring to episodes occurring during the index hospitalization after liver transplant. Chronic kidney disease was defined as abnormalities of kidney structure or function, persisting for at least 3 months, with postoperative CKD referring to an eGFR <60 mL/min/1.73 m² for ≥3 months at any point during follow-up after liver transplant. Postoperative ESRD was defined as the requirement for permanent dialysis or renal transplantation. Patients with a pretransplant eGFR <90 mL/min/1.73 m² were classified as having preoperative CKD. Because only 4 patients had a pretransplant eGFR <60 mL/min/1.73 m², this higher threshold was chosen to allow meaningful statistical analysis. The primary outcomes were the development of postoperative CKD, ESRD, and 10-year all-cause mortality. We used SPSS Statistics version 25.0 (IBM Corp) for statistical analyses. We expressed continuous variables as mean ± SD or median (interquartile range) and categorical variables as frequencies and percentages. For group comparisons, we used appropriate parametric or nonparametric tests for continuous variables and the χ2 or the Fisher exact test for categorical variables. We conducted multivariate logistic regression analyses to identify independent predictors of postoperative CKD, ESRD, and 10-year mortality. We evaluated survival using the Kaplan-Meier method, with comparisons made with the log-rank test. We used receiver operating characteristic curve analysis to determine optimal cutoff values, defined as the point with the highest combined sensitivity and specificity. P < .⁰⁵ was considered statistically significant.

Results
During the study period, 188 orthotopic liver transplants were performed in adult recipients. Excluded patients included 6 patients transplanted for indications other than chronic liver disease, 1 with oxalosis underwent simultaneous liver-kidney transplant, and 2 patients with ESRD at the time of transplant. The final cohort comprised 179 adult liver transplant recipients, with a mean age of 43 ± 14 years, 72% male, and mean posttransplant follow-up of 120 ± 76 months. At the time of transplant, 14.5% of patients were classified as Child-Pugh A, 37.4% as Child-Pugh B, and 48.1% as Child-Pugh C. Living donor grafts were used in 68.2% of patients. Primary transplant was performed in 96.1% of patients and 3.9% underwent retransplant. Baseline demographic and clinical characteristics are presented in Table 1. Preoperative CKD (eGFR <90 mL/min/1.73 m²) was present in 16 patients (8.9%). Compared with patients without renal dysfunction, patients with preoperative CKD had higher rates of preoperative hypertension (37.5% vs 6.8%), hepatorenal syndrome (31.3% vs 7.4%), and early postoperative AKI (93.8% vs 54.0%) (all P < .⁰⁵). Importantly, 81% of these patients subsequently progressed to postoperative CKD (eGFR <60 mL/min/1.73 m²). At the end of the 10-year follow-up, CKD had developed in 43 patients (24%) and ESRD in 12 patients (6.7%). Overall, 60 patients (33.5%) died during follow-up. Table 2 summarizes the clinical characteristics and outcomes according to postoperative CKD status. No significant associations were observed between the development of postoperative CKD and the etiology of liver disease, Child-Pugh class, MELD-Na score, or cirrhosis-related complications (all P > .⁰⁵). Because patients in groups with and without CKD status were exposed to iodinated contrast agents postoperatively, comparison of exposure prevalence was not possible. The number of iodinated contrast administrations was not associated with postoperative CKD (P = .⁸⁷⁹). Similarly, neither gadolinium-based contrast exposure (P = .¹⁸⁰) nor repeated exposure (P = .³⁷⁹) was associated with CKD development. Independent predictors of postoperative CKD identified by multivariable logistic regression analysis are presented in Table 3. Age and the number of AKI episodes were also analyzed as dichotomous variables. Recipient age of 43 years or older was associated with an increased risk of postoperative CKD, with an odds ratio (OR) of 7.37 (95% CI, 1.92-28.33; P = .⁰⁰⁴). Similarly, patients who experienced 5 or more AKI episodes had a significantly higher risk of CKD (OR of 4.50; 95% CI, 1.61-12.55; P = .⁰⁰⁴). Table 4 summarizes the 10-year trajectory of serum creatinine levels and eGFR in the overall cohort, with subgroup analyses according to preoperative CKD and postoperative CKD status, along with the annual number of patients under follow-up. Figure 1 illustrates the annual eGFR values over the 10-year follow-up in patients who developed postoperative CKD (eGFR <60 mL/min/1.73 m²). Preoperative CKD was not significantly associated with ESRD development (P = .³³¹). Patients who developed ESRD were more often ≥43 years old (83.3% vs 54.0%; P = .⁰⁴⁷), had more postoperative AKI episodes (7 ± 3 vs 4 ± 3; P = .⁰⁰⁷), more frequently received nephrotoxic antibiotics (83.3% vs 46.1%; P = .⁰¹⁶), and had higher rates of postoperative hypertension (66.7% vs 29.9%; P = .⁰²⁰). Liver graft rejection rates were significantly lower in patients with preoperative CKD (12.5% vs 49.1%), postoperative CKD (30.2% vs 50.7%), and ESRD (8.3% vs 48.5%) compared with patients without these conditions (all P < .⁰⁵). Postoperative mean lymphocyte counts were also significantly lower in patients with preoperative CKD (0.33 ± 0.26 vs 0.85 ± 1.20 ×10³/µL) and postoperative CKD (0.65 ± 0.64 vs 0.85 ± 1.27 ×10³/µL) than in patients without these conditions (P < .⁰⁵). In multivariable analysis, nephrotoxic antibiotic use (OR 7.21; 95% CI, 1.43-36.26; P = .⁰¹⁷) and postoperative hypertension (OR 5.70; 95% CI, 1.50-21.65; P = .⁰¹¹) were identified as independent predictors of ESRD. Factors associated with 10-year mortality are summarized in Table 5. The rates of early postoperative AKI and postoperative CKD did not differ significantly between survivors and nonsurvivors. End-stage renal disease occurred in 10% of nonsurvivors and 5% of survivors; however, this difference was not significant (P = .²¹¹). In multivariable Cox regression analysis, hepatitis C virus infection (hazard ratio 5.34; 95% CI, 1.60-17.78; P = .⁰⁰⁶) and hepatocellular carcinoma (hazard ratio 2.60; 95% CI, 1.23-5.49; P = .⁰¹²) were independently associated with increased 10-year mortality. In addition, mortality risk increased by 11% with each additional postoperative infection episode (hazard ratio 1.11 per episode; 95% CI, 1.03-1.19; P = .⁰⁰⁵). Kaplan-Meier survival analysis demonstrated significantly reduced overall survival in recipients with hepatitis C virus infection and in those with hepatocellular carcinoma compared with patients without these conditions (both log-rank P < .⁰⁰¹). In addition, overall survival declined progressively with increasing postoperative infection burden, with the poorest outcomes observed in patients who experienced ≥6 infection episodes (log-rank P < .⁰⁰¹) (Figure 2).

Discussion
Liver transplant markedly improves long-term survival in patients with end-stage liver failure; however, CKD and ESRD remain important late complications. The present study assessed the determinants of long-term renal outcomes and their association with survival, as well as independent risk factors for mortality after liver transplant. Postoperative hypertension and nephrotoxic antibiotic exposure were the strongest independent predictors of both CKD and ESRD. Advanced recipient age, recurrent postoperative AKI episodes, and cyclosporine use were additionally associated with CKD development. These findings highlight the combined effects of hemodynamic stress and cumulative nephrotoxic exposure on progressive renal impairment after transplant. Renal dysfunction was not independently associated with increased long-term mortality. Instead, hepatitis C virus infection, hepatocellular carcinoma, and recurrent postoperative infections were the principal determinants of 10-year mortality, emphasizing the multifactorial nature of late posttransplant outcomes. Notably, graft rejection rates were lower among recipients with preoperative CKD and postoperative CKD or ESRD, and these patients had lower postoperative lymphocyte counts. This finding may reflect differences in immunosuppressive intensity, altered immune responsiveness, or more cautious immunosuppressive strategies in patients with impaired renal function. Renal function followed a biphasic pattern, with a marked reduction during the first postoperative year and a slower decline thereafter. The early decrease likely reflects perioperative hemodynamic stress and calcineurin inhibitor exposure, whereas long-term progression may be related to cumulative nephrotoxicity caused by persistent hypertension and recurrent AKI episodes in susceptible recipients.^15,16 Older recipient age was independently associated with postoperative CKD, consistent with prior reports.^17,18 Alcohol consumption has been implicated in renal dysfunction through mechanisms that include tubular injury, oxidative stress, and fluid-electrolyte imbalance.^19-22 Alcohol can exacerbate chronic liver disease by interacting synergistically with other hepatic insults, thereby increasing the risk of postoperative renal dysfunction.²³ In our cohort, alcohol use was independently associated with postoperative CKD, supporting the presence of preexisting renal vulnerability in this subgroup. Hepatitis B virus (HBV) infection has been associated with renal dysfunction, including proteinuria and CKD, and hepatitis B immunoglobulin therapy after transplant may further increase nephrotoxicity, particularly when combined with other nephrotoxic agents.^24,25 In our cohort, HBV infection was independently associated with postoperative CKD, suggesting that both disease-related and treatment-related mechanisms may contribute to renal vulnerability in this population. Recurrent AKI is a recognized driver of CKD after liver transplant, reflecting the bidirectional relationship between acute and chronic renal injury.^26,27 In our cohort, AKI most frequently occurred in the context of infections, and patients with ≥5 AKI episodes had a 4.5-fold increased risk of developing postoperative CKD, underscoring the cumulative effect of repeated renal insults. Cyclosporine has been associated with chronic nephrotoxicity after liver transplant, although the renal effects of calcineurin inhibitors remain debated.^28-30 In our cohort, cyclosporine use was independently associated with postoperative CKD. Tacrolimus was the primary initial immunosuppressive agent; however, in patients who developed renal dysfunction or de novo malignancy, calcineurin inhibitors were reduced or discontinued and switched to mechanistic target of rapamycin inhibitors. The higher use of mechanistic target of rapamycin inhibitors in the CKD group likely reflects treatment adjustments rather than a causal effect. Chronic kidney disease is associated with immune dysregulation driven by uremia, chronic inflammation, and reduced active vitamin D synthesis. Impairment in T-cell number and function, along with features of premature immunologic aging, has been well documented in this population.^31,32 This altered immune milieu may attenuate alloimmune responses under standard immunosuppression. In our cohort, rejection rates were significantly lower among patients with preoperative renal dysfunction and in those who developed postoperative CKD or ESRD compared with recipients without renal impairment. Although HLA subtypes and panel reactive antibody levels were not routinely available, lower postoperative lymphocyte counts in patients with CKD support the presence of relative immune suppression, which may partly explain the reduced rejection rates. Recurrent postoperative AKI episodes were strongly associated with progression to ESRD. Although the overall infection burden was not directly associated with ESRD, exposure to nephrotoxic antibiotics independently predicted both CKD and ESRD, underscoring the cumulative effect of renal injury. Hypertension is a common complication after liver transplant, often related to calcineurin inhibitor-based immunosuppression and contributing to long-term renal dysfunction.^33,34 Importantly, postoperative hypertension independently predicted both CKD and ESRD in our cohort, underscoring its central role in progressive renal injury in this setting. Although early mortality after liver transplant is primarily attributable to allograft-related complications, late mortality is increasingly driven by posttransplant comorbidities.³⁵ Infection remains a major cause of mortality after liver transplant, particularly during periods of intensified immunosuppression.^36,37 A recent large cohort study identified the burden of postoperative infections as a key determinant of posttransplant survival.³⁸ Consistent with these findings, we observed that the cumulative number of postoperative infections independently predicted 10-year mortality. In our study, hepatocellular carcinoma independently predicted long-term mortality. Although transplant selection is guided by Milan criteria, additional tumor-related factors, such as microvascular invasion, histological differentiation, and biological markers, also affect posttransplant outcomes.³⁹ Thus, the increased mortality in patients with hepatocellular carcinoma likely reflects tumor biology beyond size- and number-based criteria. In our cohort, hepatitis C virus infection independently predicted long-term mortality, likely reflecting patients who had been transplanted before the widespread use of direct-acting antivirals, when interferon-based regimens were associated with high posttransplant recurrence and limited virological response.⁴⁰ The adverse effect of hepatitis C virus in our study thus mainly reflects outcomes before direct-acting antivirals. Postoperative CKD has been associated with increased cardiovascular burden and reduced long-term survival after liver transplant, particularly when eGFR declines below 60 mL/min/1.73 m².16,^41,42 In contrast, we did not observe a significant association between postoperative CKD and 10-year mortality. Although ESRD was numerically more frequent among those who did not survive, the relatively small number of ESRD cases in our cohort may have limited the statistical power to detect a significant difference. This study had several strengths, including a 25-year study period with long-term follow-up, allowing a comprehensive assessment of CKD, ESRD, and mortality after liver transplant. Renal outcomes were evaluated as distinct endpoints, and their relationship with long-term survival was specifically examined. The retrospective, single-center design and the small number of patients with preoperative renal dysfunction limited the generalizability and statistical power of our findings. In addition, the lack of comprehensive renal evaluation, including urinary parameters, may have restricted assessment of kidney function. Prospective, multicenter studies are needed to validate these results. Renal dysfunction remains a major long-term determinant of morbidity in liver transplant recipients. Advanced age, recurrent postoperative AKI, nephrotoxic antibiotics, and postoperative hypertension were key factors associated with CKD and ESRD. Renal-protective immunosuppression, careful infection management, and strict cardiovascular risk control may help preserve kidney function. Early identification of high-risk patients and individualized follow-up are essential. The lower rejection rates observed in patients with renal dysfunction further suggest that CKD-related immune alterations may modulate posttransplant alloimmune responses.