Objectives: Hepatorenal syndrome is a severe com-plication of end-stage liver disease, associated with poor prognosis and increased risk of renal dysfunction after liver transplant. With the effects of hepatorenal syndrome on outcomes after living donor liver transplant not yet fully established, we conducted a systematic review to evaluate the effect of hepa-torenal syndrome on posttransplant outcomes.
Materials and Methods: We searched PubMed, Embase, and Cochrane for studies comparing living donor liver transplant outcomes in patients with and without hepatorenal syndrome. We used risk ratios for binary outcomes and mean differences for continuous variables. P < .05 was considered significant. We used R Studio 4.3.1 with a random-effects model to conduct the statistical analyses.
Results: In 4 retrospective studies on living-donor liver transplant, which included 2931 patients, patients with (n = 313; 10.7%) and without hepatorenal syndrome were compared. The hepatorenal syndrome group had significantly lower 5-year patient survival (risk ratio 0.91; 95% CI, 0.85-0.95; P = .005), higher hospital mortality (risk ratio 2.38; 95% CI, 1.52-3.72; P < .001), increased posttransplant bleeding (risk ratio 2.32; 95% CI, 1.45-3.69; P < .001), and greater need for renal replacement therapy (risk ratio 9.4; 95% CI, 5.46–16.19; P < .001). No significant difference was found for hospital stay duration (mean difference 19.24 days; P = .44). A meta-regression of the effect of the Model for End-Stage Liver Disease score on 5-year patient survival also showed no significant association. In the proportional analysis of only patients with hepatorenal syndrome, pooled 5-year patient survival was 77.02 per 100 observations (95% CI, 64.26-86.20), whereas pooled incidence of renal replacement therapy was 27.40 per 100 observations (95% CI, 12.41-50.15).
Conclusions: Living-donor liver transplant in patients with hepatorenal syndrome carries a higher risk of hospital mortality and early posttransplant compli-cations, with reduced 5-year survival.

Key words : Early posttransplant complications, Liver transplantation, Survival

Introduction

Hepatorenal syndrome (HRS) is a severe complication of end-stage liver disease, defined as a functional renal failure resulting from renal vasoconstriction secon-dary to hepatic deterioration.¹ Hepatorenal syndrome can occur spontaneously without secondary altera-tions or can be triggered by a precipitating factor.² Hepatorenal syndrome is typically classified into 2 subtypes: HRS-acute kidney injury (HRS-AKI), marked by rapid renal function decline and being the most severe form of AKI in cirrhosis, and HRS-chronic kidney disease (HRS-CKD), which manifests as a more gradual and chronic impairment of kidney function in patients with cirrhosis, associated with higher survival rates.^3,4
Liver transplant (LT) is considered the most effective and definitive treatment for HRS, particularly as a result of the established role of LT in promoting renal recovery.⁵ However, the critical shortage of organs and the high demand for deceased donor liver transplant (DDLT) have resulted in prolonged waiting times.^2,6 These factors are especially concerning, as extended dialysis duration is associated with reduced posttransplant survival. Consequently, living donor liver transplant (LDLT) has emerged as a potential alternative to mitigate waitlist mortality and opti-mize treatment outcomes.⁷
Concerns about LDLT, in the setting of the high metabolic demand associated with HRS, include that LDLT may not achieve the same outcomes as DDLT.^8,9 Therefore, we conducted a systematic review and meta-analysis to evaluate the effect of HRS in patients undergoing LDLT compared with non-HRS patients.

Materials and Methods

We conducted this systematic review and meta-analysis per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.¹⁰ The study protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420250654887).

Search strategy and eligibility criteria
We systematically searched the MEDLINE, Embase, and Cochrane databases from inception to April 2025 for studies that allowed us to compare LDLT outcomes in patients with HRS and without HRS by using the following search strategy: “hepatorenal syndrome” OR “pretransplant hepatorenal” OR “hepatic-renal syndrome” AND “Liver Transplantation” OR “liver transplant” OR “hepatic transplant” OR “hepatic transplantation” OR “liver graft” AND “Living Donors” OR “living donor” OR “LDLT” OR “living-donor”.
Three authors (PV, MCM, and GFM) indepen-dently conducted the literature search. We included studies that met the following criteria: (1) rando-mized controlled trials or observational cohort studies, (2) studies that compared LDLT outcomes between patients with and without HRS, and (3) studies that reported at least 1 endpoint of interest. We excluded conference abstracts and included only studies published in English. We applied no restrictions regarding publication date.

Endpoints of interest and data extraction
Three authors (PV, JEP, and EDJ) conducted the data extraction from eligible studies. We included the following endpoints of interest: (1) patient survival in 5 years, (2) hospital mortality, (3) bleeding occurrence after liver transplant, (4) need for renal replacement therapy (RRT), and (5) hospital length of stay (in days).
We also collected the following information from each study: study design, cohort year, number of patients, sex distribution, age, Model for End-Stage Liver Disease (MELD) scores, serum creatinine (sCr) levels, and follow-up time.

Statistical analyses
We used risk ratios (RR) for binary outcomes and mean differences for continuous variables. P < .05 was considered significant. We used R Studio 4.3.1 with a random-effects model to conduct the analyses. We conducted a subgroup analysis to compare outcomes between HRS responders and nonresponders; HRS responders were defined as patients who recovered from HRS, indicated by an estimated glomerular filtration rate ≥ 60 mL/min/1.73m² or sCr ≤ 1.5 mg/day and resolution of the need for RRT.
We performed a meta-regression of MELD score on 5-year patient survival. We also conducted leave-1-out analysis to understand the potential influence of each study on 5-year patient survival. We also conducted proportional analyses on only patients with HRS to estimate the pooled incidence of RRT and 5-year patient survival. For this analysis, the number of events per 100 observations and corresponding 95% CIs were calculated using a random-effects model.

Quality assessment
Two authors (MCM and GFM) independently eva-luated the risk of bias for each study using the Cochrane Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I).¹¹ Disagreements were resolved through consensus.

Results

Study selection and patient characteristics
As shown in Figure 1, our study analyzed 4 retrospective studies on LDLT, spanning from 1994 to 2019 (n = 2931 patients), to compare HRS (n = 313; 10.7%) and non-HRS groups.^12-15 Mean age ranged from 49.0 to 53.7 years in the HRS group and from 42.0 to 53.7 years in the non-HRS group, with MELD score ranging from 21.1 to 41.9 and 13.9 to 33.6, respectively. Table 1 lists study characteristics.

Pooled analysis of included studies
The HRS group had significantly lower 5-year patient survival (RR 0.91; 95% CI, 0.85-0.95; P = .01; I²=14.9%; Figure 2A), higher hospital mortality (RR 2.38; 95% CI, 1.52-3.72; P < .001; I²=0%; Figure 2B), increased posttransplant bleeding (RR 2.32; 95% CI, 1.45-3.69; P < .001; I²=41.6%; Figure 3A), and greater need for RRT (RR 9.4; 95% CI, 5.46-16.19; P < .001; I²=45.9%; Figure 3B). No significant difference was found for hospital stay duration (mean difference 19.24 days; 95% CI, -28.74 to 67.22 days; P = .44; I²=0%; Figure 4).
In the subgroup analysis on HRS responders (n = 142) compared with nonresponders (n = 109), no difference was found between the groups in 5-year patient survival (RR 0.77; 95% CI, 0.50-1.17; P = .01; I²=85.6%; Figure 5). A meta regression of MELD score on 5-year patient survival also showed no significant association (Figure 6). Furthermore, in the leave-1-out analysis, we found that none of the included studies was associated with a significant difference in the overall pooled estimate (Figure 7).
In our proportional analysis, which included only HRS patients, the pooled 5-year patient survival was 77.02 per 100 observations (95% CI, 64.26-86.20; I²=73.6%; Figure 8A), whereas the pooled incidence of RRT was 27.40 per 100 observations (95% CI, 12.41-50.15; I²=89.3%; Figure 8B).

Quality assessment
Overall, 3 studies exhibited a moderate risk of bias, and 1 study was rated as having a serious risk of bias.^12,14,15 The primary source of serious bias in the Okamura study was related to domain 1, regarding confounding factors.¹³ Moderate bias was commonly observed across all studies in several domains, including selection of participants, deviations from intended interventions, and selection of reported results. Bias because of missing data and classification of interventions was predominantly rated as low across all studies. Measurement of outcomes was con-sistently at low risk of bias, except for the Okamura study, which showed moderate risk in this domain. These findings indicated that, although most studies had moderate bias, the presence of serious con-founding in 1 study may have affected the overall certainty of the evidence (Figure 9).

Discussion

To our knowledge, this was the first systematic review and meta-analysis that assessed the impact of HRS on outcomes in LDLT. Our findings indicated that HRS was associated with worse posttransplant outcomes, including reduced 5-year survival, in-creased in-hospital mortality, higher need for RRT, and greater risk of posttransplant bleeding. These findings highlight the complexity of managing HRS in the transplant setting and reinforce the need for further strategies to optimize outcomes in this high-risk population.
Although LDLT has traditionally been considered a secondary option to DDLT, LDLT has gained increasing prominence, particularly in regions with organ shortages.⁸ Compared with DDLT, LDLT enables faster transplant, potentially reducing the risk of deterioration associated with prolonged wait times.^8,16,17 Grafts from living donors also typically have minimal ischemia time and are retrieved under controlled conditions, which may mitigate ischemia-reperfusion injury.^16,17 Moreover, LDLT allows for planned transplant, ensuring optimal pretransplant management, including renal function assessment and fluid status optimization. Altogether, these features make LDLT a valuable therapeutic option, despite the increased technical complexity and donor-related considerations.
Although LDLT may provide patients timely access to transplant, alternative strategies to optimize DDLT have also emerged.¹⁸ Notably, normothermic machine perfusion has been shown to improve graft preservation, reduce early allograft dysfunction, and reduce the need for RRT.^19,20 These advancements could broaden the applicability of DDLT to higher-risk recipients, including those with HRS, and may reduce reliance on LDLT in some settings. Machine perfusion and the ability to preserve marginal grafts hold promise for expanding the donor pool.
The optimal timing of transplant in patients with HRS remains a matter of debate in the literature, particularly given the delicate balance between the risks associated with prolonged waiting and the potential benefits of early transplant. Delaying transplant may allow for partial renal function recovery but carries the risk of progressive hepatic and renal decompensation.^14,21,22 For instance, Park and colleagues showed that an interval of 38 days or more between HRS diagnosis and transplant was significantly associated with a lower likelihood of renal recovery.¹⁴ This highlights the importance of individualized assessment to balance urgency with readiness, particularly in patients who may respond to medical management before transplant.
Survival outcomes in patients with HRS under-going LDLT remain controversial. Although our findings suggested increased mortality in this group, previous studies have reported comparable survival between LDLT and DDLT in well-selected HRS patients.^8,15 However, the presence or absence of preoperative renal recovery appears to influence prognosis, as demonstrated by Park and colleagues, with persistent HRS associated with worse renal outcomes and a higher likelihood of posttransplant CKD.¹⁴ These findings suggest that, although LDLT can be effective in improving kidney function, careful evaluation of renal function before transplant plays an important role in shaping posttransplant survival.
Our proportional analysis focusing on HRS patients offered valuable insights into our findings. Despite the high rate of RRT, the 5-year survival rate approaching 80% suggests that LDLT can still provide meaningful long-term benefits in this group. These findings underscore the potential benefit of pretransplant medical optimization. In addition, interventions such as terlipressin and albumin infusion may reduce the burden of perioperative renal dysfunction.^23,24 Thus, comprehensive preope-rative assessment and early intervention remain cornerstones of successful outcomes.
Increased bleeding risk is another important complication in the HRS population.¹⁴ This risk likely reflects the combination of coagulopathy, portal hypertension, and renal impairment commonly seen in these patients.^25,26 Intraoperative factors such as transfusion needs and prolonged operative times may also contribute.¹⁴ These observations highlight the importance of meticulous surgical planning and perioperative hemostatic management to minimize bleeding-related morbidity.
Although preoperative renal recovery did not appear to significantly affect long-term survival in our analysis, preoperative renal recovery may still reduce immediate postoperative complications and facilitate early stabilization. Some reports have suggested that even transient renal improvement before transplant can lower the risk of chronic kidney injury and improve metabolic resilience.^15,27,28 The role of renal recovery in influencing long-term prognosis remains an open question and warrants further investigation, particularly through studies incorpora­ting renal biomarkers and granular functional data.
Although our study provided important findings, some limitations should be acknowledged. To our knowledge, this is the first meta-analysis to compare outcomes in LDLT between patients with and without HRS. However, all included studies were nonran-domized and were potentially associated with confo-unding factors. In addition, although the subgroup analysis on HRS responders provided additional insights, the analysis was limited by the small number of studies, limiting the generalizability of our findings. Moreover, as a result of limited available data, we could not differentiate the impact of HRS-AKI versus HRS-CKD and analyze certain key outcomes, such as primary graft nonfunction, postreperfusion syndrome, biliary complications, and especially liver failure after transplant, which could have enriched our analysis.

Conclusions

Our findings suggest that LDLT in patients with HRS carries a higher risk of hospital mortality and early posttransplant complications, with reduced 5-year survival compared with non-HRS patients. Nonetheless, our proportional analysis demonstrated a high pooled 5-year survival rate and a low incidence of posttransplant renal replacement therapy among this high-risk patient population.

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