Vasopressin and fluid retention after liver resection: Comparison with the renin-angiotensin-aldosterone system by surgical extent and liver function

Abstract

BACKGROUND

Early postoperative edema and ascites after liver resection are common; however, the endocrine drivers of water retention are not fully defined. Arginine vasopressin (AVP) promotes antidiuresis via V2-mediated aquaporin trafficking, whereas the renin-angiotensin-aldosterone system primarily modulates sodium handling. Differences in postoperative trajectories and their relationship to early fluid retention have not been clarified in patients undergoing liver resection.

AIM

To examine postoperative changes in plasma AVP and plasma aldosterone concentration (PAC) after liver resection, and association with fluid retention.

METHODS

We conducted a prospective cohort study of adults undergoing elective liver resection at a tertiary center. Blood samples were collected preoperatively, immediately post-resection, and on postoperative days (POD) 1, 2, 3, and 5. The primary objective was characterizing postoperative dynamics of AVP and PAC. Secondary objectives evaluated their temporal alignment with early fluid retention (body weight, urine output during POD 1-3) and compared hormonal profiles between major and minor resections. Analyses used trajectory and time-based comparisons by resection extent.

RESULTS

AVP increased sharply immediately after resection and remained above the preoperative baseline through POD 3, showing the most pronounced and sustained elevation after major liver resection. In contrast, PAC showed a transient postoperative increase that returned to near-baseline levels by POD 2. The period of elevated AVP closely matched the time frame during which early postoperative fluid retention was most evident, as indicated by greater short-term weight gain and reduced urine output. These patterns were consistent across sensitivity analyses and showed similar directional trends in subgroup comparisons based on resection extent.

CONCLUSION

AVP remains elevated longer than aldosterone and coincides with early fluid retention, particularly after major resection. Vasopressin-driven antidiuresis may be important in postoperative water retention.

Key Words: Hepatectomy; Liver resection; Vasopressin; Aldosterone; Fluid management; Water retention; Liver surgery

Core Tip: This study prospectively assessed postoperative changes in arginine vasopressin (AVP) and plasma aldosterone concentration (PAC) after liver resection and found that AVP elevation persisted longer than PAC elevation, particularly after major resections. The duration of elevated AVP closely matched the period of early postoperative fluid retention, highlighting the important role of AVP beyond the renin-angiotensin-aldosterone system. These findings suggest that targeting the V2 signaling pathway may offer strategies for optimizing fluid management and reducing complications in high-risk patients undergoing liver resection. A detailed understanding of postoperative hormonal changes is crucial for future clinical trials and therapeutic decisions.

INTRODUCTION

Liver resection has been established as a curative surgery for primary or metastatic liver tumors and is an important treatment option for certain benign diseases. Advances in surgical techniques and improvements in perioperative management have increased surgical safety; however, postoperative complication rates (Clavien-Dindo classification[1] ≥ IIIa) remain relatively high at approximately 8.5%-11%, with a mortality rate of 1.3%-5%[2-5].

Fluid retention, such as ascites and edema, is a frequent postoperative complication that poses a challenge for postoperative management. In particular, a postoperative weight gain of 3.5 kg or more is considered an independent risk factor for postoperative complications[6]. In Japan, anti-aldosterone drugs that suppress the renin-angiotensin-aldosterone system (RAAS), such as canrenoate and spironolactone, have been empirically used since the 1980s to prevent excessive postoperative fluid retention[7]. It has long been reported that the RAAS is activated in patients with ascites caused by liver cirrhosis[8]. Furthermore, Kobayashi et al[9] reported that in cases complicated by liver cirrhosis, the postoperative plasma aldosterone concentration (PAC) increases significantly and that anti-aldosterone drugs improve the urinary sodium-to-potassium ratio and reduce fluid retention.

This clinical experience has also been reflected in recent guidelines for liver cirrhosis issued by the Japan Society of Gastroenterology, which designate spironolactone as the first-line drug[10]. Consistently, major international guidelines for cirrhosis including the American Association for the Study of Liver Diseases Practice Guidance[11] and the European Association for the Study of the Liver Clinical Practice Guidelines[12] also recommend aldosterone antagonists, particularly spironolactone, as the first-line diuretic therapy for cirrhotic ascites. However, some patients exhibit insufficient diuretic response or develop adverse effects such as renal impairment or hyperkalemia when treated with mineralocorticoid receptor antagonists. It has long been suggested that, in addition to the RAAS, arginine vasopressin (AVP) contributes to fluid retention associated with liver cirrhosis[13,14], and inappropriate AVP secretion has also been reported in animal models[15]. These findings indicate that both the RAAS and vasopressin axes are intricately involved in body fluid regulation in cirrhosis and may influence postoperative water balance after liver resection.

Classical studies have reported that plasma vasopressin levels transiently increase during laparotomy, thoracotomy, and laparoscopic surgery, reflecting the magnitude of surgical stress[16,17]. However, little is known about AVP dynamics during liver resection or its association with postoperative fluid retention. This study aimed to elucidate the postoperative hormonal dynamics of AVP and PAC and clarify their relationship with postoperative fluid retention following liver resection.

MATERIALS AND METHODS

We included 56 consecutive patients who underwent hepatic resection at our hospital between March 2019 and October 2019. This non-interventional prospective study was approved by the Ethics Committee of Nippon Medical School Hospital[18] (approval No. 30-01-1070). Written informed consent was obtained from all patients, and data were collected prospectively.

Perioperative management followed the standard institutional protocol. The exclusion criteria included emergency surgery, dialysis-dependent renal failure, and cases requiring renal replacement therapy during the perioperative period. The primary endpoints were temporal changes in PAC and AVP levels, whereas the secondary endpoints were postoperative body weight gain, urine output, and drain discharge volume. Immediately after surgery, patients were admitted to the intensive care unit (ICU) for fluid management under strict monitoring. If there were no abnormalities, the patients were transferred to the general ward the following day. Fluid infusion was generally maintained at 1500-2000 mL/day. Oral intake was initiated on postoperative day (POD) 2, followed by gradual reduction or discontinuation of intravenous infusion based on the intake volume.

According to the standard protocol, 200 mg of potassium canrenoate was administered intravenously in the morning immediately after surgery and again on POD 1 and 2. Oral spironolactone (25 mg/day) was initiated on POD 1.

Assessment of fluid dynamics

Body weight, urine output (mL/kg), and drain discharge volume (mL/kg) were recorded daily. The patient background characteristics (age, sex, underlying disease, liver function indices, and surgical procedures) are presented in the results section. Maximum postoperative weight gain (%) was defined as 100 × (maximum postoperative body weight - preoperative body weight)/preoperative body weight. Intraoperative fluid balance (mL/kg/hour) was calculated as (total infused fluids - blood loss - urine output)/body weight/operative time.

Hormone measurement

PAC and AVP were measured preoperatively (baseline), immediately after surgery, and in the morning on POD 1, 2, 3, and 5 after at least 10 minutes of rest in the supine position. Measurements were outsourced to BML Inc. (Tokyo, Japan). PAC was measured by chemiluminescent enzyme immunoassay (pg/mL); AVP, double-antibody radioimmunoassay (RIA) (pg/mL); and plasma renin activity (PRA), enzyme immunoassay (ng/mL/hour).

Grouping

Stratification by liver function was based on the indocyanine green retention rate at 15 minutes (ICG_R15), with patients with values < 10% and ≥ 10% defined as the normal liver (NL) and impaired liver (IL) groups, respectively.

Following conventions used in literature referencing the Brisbane 2000 terminology[19], major liver resection (MajLR) was defined as resection of ≥ 3 Couinaud segments. In this cohort, the MajLR group included patients who underwent right or left hemihepatectomy and left trisectionectomy but did not undergo central bisectionectomy. Minor liver resection (MinLR) was defined as resection of < 3 segments (sectionectomy or less). Patients were categorized accordingly.

Statistical analysis

Statistical analyses were performed using JMP Pro 18.0.2 (SAS Institute, Cary, NC, United States). Hormone levels over time were compared using the Wilcoxon signed-rank test for differences between preoperative values and each postoperative time point, and the Mann-Whitney U test was used for intergroup comparisons. Continuous variables were expressed as mean ± SD or median (interquartile range), depending on the distribution. Body weights, which followed a normal distribution, were compared using a paired t-test. Post-hoc urine output on POD 1 and POD 2 was compared between patients with and without hypervasopressinemia on POD 1 using the unpaired Student t-test as the data were normally distributed. A two-sided P value < 0.05 was considered statistically significant. Given the exploratory nature of this study, no adjustments for multiple comparisons were made. The cut-off for hypervasopressinemia (AVP ≥ 4.0 pg/mL) was determined according to the reference range specified by the assay provider (double-antibody RIA). Missing data were handled using complete-case analysis, and no outlier exclusion was performed.

RESULTS

All cohort

This study included 56 patients (37 men and 19 women) with a median age of 69 years. Primary indications for liver resection were colorectal liver metastasis (CRLM) (n = 25) and hepatocellular carcinoma (HCC) (n = 20). Based on liver function, there were 29 and 27 patients in the IL group (ICG_R15 ≥ 10%) and NL group (ICG_R15 < 10%), respectively. Based on the surgical procedure, there were 11 and 45 cases of MajLR and 45 MinLR, respectively. A laparoscopic approach was used in 22 patients. Extrahepatic bile duct resection was performed in four cases, and concomitant colorectal resection was performed in three cases. The median intraoperative fluid balance was 8.1 mL/kg/hour, and the median operative time was 295 minutes (Table 1). Regarding medications that could influence RAAS or water balance, spironolactone was taken preoperatively by 9 patients, all of whom belonged to the IL group. Angiotensin II receptor blockers were used by 15 patients (27%), with no notable differences among the IL, NL, MajLR, or MinLR groups. Two patients in the IL group were taking angiotensin-converting enzyme inhibitors. No patients were receiving tolvaptan preoperatively.

Table 1 Baseline characteristics of the study cohort, mean ± SD/n (%).

Characteristics	All patients (n = 56)
Age (years), median (IQR)	69 (64-75)
Sex (men/women)	37 (66.0)/19 (33.9)
Indication of liver resection
Colorectal liver metastasis	25 (44.6)
Hepatocellular carcinoma	20 (35.7)
Biliary tract cancer	5 (8.9)
Others	6 (10.7)
Indocyanine green retention rate at 15 minutes (%), median (IQR)	10.2 (7.2-14.5)
Kinetic indocyanine green elimination rate constant, median (IQR)	0.155 (0.129-0.177)
Fibrosis-4 index, median (IQR)	1.82 (1.21-3.06)
Albumin-bilirubin scoring	-2.58 ± 0.42
Modified ALBI grade (1/2a/2b/3)	26 (46.4)/18 (32.1)/12 (21.4)/0 (0)
Number of complete resected Couinaud segments, median (IQR)	0 (0-2)
Laparoscopic surgery	22 (39.3)
Extrahepatic bile duct resection	4 (7.1)
Concomitant colorectal resection	3 (5.4)
Operative duration (minutes), median (IQR)	295 (224-379)
Intraoperative blood loss (mL), median (IQR)	333 (100-600)
Intraoperative red blood cell transfusion	11 (19.6)
Intraoperative fluid balance (mL/kg/hour), median (IQR)	8.1 (6.4-11.9)
Preoperative body weight (kg), median IQR	58.2 (52.6-66.4)
Maximum postoperative weight gain (%), median (IQR)	2.7 (1.1-6.4)
Complications (Clavien-Dindo grade ≥ IIIa) (%)	12 (21.4)

IQR: Interquartile range; ALBI: Albumin-bilirubin.

Postoperatively, tolvaptan was administered in 4 patients, all of whom were in the IL group; two of these were in the MajLR group. Furosemide was used postoperatively in 12 patients (21%), with no significant differences between MajLR and MinLR (22% vs 18%) or between the IL and NL groups (28% vs 15%). Postoperative complications of Clavien-Dindo grade ≥ IIIa occurred in 12 patients (21%), half of whom were in the MajLR group.

When examining the overall time course for all cases, body weight increased significantly from a preoperative value of 60.3 ± 12.0 kg to a postoperative peak of 62.3 ± 11.8 kg (P < 0.001). However, by POD 5, this difference disappeared (P = 0.264), with a peak in weight gain observed between POD 2 and 3. Urine output also increased from POD 2 (33.4 ± 14.9 mL/kg body weight) to POD 3 (34.1 ± 13.6 mL/kg body weight) and then gradually decreased. Serum sodium concentration showed a transient rise from 140.4 ± 2.6 mEq/L preoperatively to 142.0 ± 2.5 mEq/L immediately after surgery (P < 0.001) and then decreased to a minimum at POD 2 (139.5 ± 3.0 mEq/L, P = 0.015). On POD 3 and 5, serum sodium levels generally returned to the preoperative values. The lowest and highest serum sodium concentration levels observed postoperatively were 130 mEq/L and 148 mEq/L, respectively. No cases with severe electrolyte abnormalities were identified. Urinary sodium concentration decreased postoperatively, reaching its lowest level at POD 2 (69.9 ± 47.5 mEq/L vs 113.5 ± 50.0 mEq/L preoperatively; P < 0.001), and by POD 5, it was no longer different from the preoperative values. Serum osmolality also increased from 284 mOsm/L (282-287 mOsm/L) preoperatively to 293 mOsm/L (289-296 mOsm/L) immediately after surgery (P < 0.001) and returned to baseline by POD 2 at 285 mOsm/L (280-287 mOsm/L) (P = 0.963).

Regarding hormonal dynamics (Figure 1), PAC was significantly elevated immediately after surgery and on POD 1 compared with preoperative values (both P < 0.001), but it returned to baseline by POD 2 (P = 0.072), with no significant differences thereafter. In contrast, AVP peaked immediately after surgery and remained significantly elevated until POD 3 compared with preoperative levels (all P < 0.001), returning to baseline by POD 5 (P = 0.926).

Figure 1 Perioperative changes in plasma aldosterone concentration and arginine vasopressin in all patients. A and B: Temporal changes in plasma aldosterone concentration (PAC) (A) and arginine vasopressin (AVP) (B) levels in all 56 patients undergoing liver resection. Both PAC and AVP increased significantly immediately after liver resection, followed by gradual normalization on postoperative day 5. Values were expressed as medians with interquartile ranges. ^aP < 0.01 vs preoperative baseline. PAC: Plasma aldosterone concentration; AVP: Arginine vasopressin; LR: Liver resection; POD: Postoperative day.

PRA was 64.8 ng/mL/hour (42.6-93.8 ng/mL/hour) preoperatively and peaked at 100.8 ng/mL/hour (74.6-122.5 ng/mL/hour) immediately after surgery (P < 0.001). Although the PRA gradually decreased thereafter, it remained elevated at POD 5 at 65.5 ng/mL/hour (52.0-78.0 ng/mL/hour) compared with baseline (P < 0.001). PAC showed a similar pattern but returned to levels not significantly different from baseline by POD 2.

Serum creatinine levels decreased slightly to 0.68 mg/dL (0.55-0.76 mg/dL) on POD 3 compared with the preoperative value of 0.69 mg/dL (0.59-0.81 mg/dL) (P = 0.040) and returned to 0.69 mg/dL (0.58-0.76 mg/dL) on POD 5 (P = 0.077), indicating no postoperative renal impairment.

These clinical changes namely postoperative weight gain, transient hyponatremia, and reduced urinary sodium excretion around POD 2 were temporally consistent with the sustained elevation of AVP, suggesting predominant free water retention in the early postoperative period.

Comparison by liver function

When comparing liver function, the median age was higher in the IL group [71 years (68-77 years) vs 66 years (60-74 years), P = 0.034], and this group included a greater proportion of patients with HCC. There were no significant differences in sex or distribution of surgical procedures between the groups. Regarding liver function indicators, the IL group showed a significantly higher fibrosis-4 (FIB-4) index[20] and worse modified albumin-bilirubin (ALBI) grade[21] compared with the NL group, whereas the ALBI score[22] tended to be higher but did not reach statistical significance (Table 2). In both the NL and IL groups, AVP levels were higher than preoperative values immediately after liver resection, and on POD 1 and POD 2 (all P < 0.001), with the elevation persisting on POD 3 (IL, P = 0.006; NL, P = 0.008). No significant differences were observed between the groups at any time point. For PAC, the IL group showed a marked increase immediately after surgery and on POD 1 (both P < 0.001). In the NL group, PAC increased only immediately after surgery (P < 0.001), with no significant differences thereafter. At all time points, there were no significant differences in PAC levels between the groups (Figure 2). No difference was observed in urine output per kilogram of body weight or in drainage output based on the presence or absence of liver dysfunction.

Figure 2 Comparison of plasma aldosterone concentration and arginine vasopressin dynamics by liver function. A and B: Changes in plasma aldosterone concentration (PAC) (A) and arginine vasopressin (AVP) (B) in patients with normal liver (NL) (blue line) and impaired liver (IL) (red line), stratified by the indocyanine green retention rate at 15 minutes (< 10% = NL; ≥ 10% = IL). Both groups exhibited postoperative elevations in PAC and AVP with no significant intergroup differences at any time point. Values are expressed as medians with interquartile ranges. NL: Normal liver; IL: Impaired liver; PAC: Plasma aldosterone concentration; AVP: Arginine vasopressin; LR: Liver resection; POD: Postoperative day.

Table 2 Comparison of perioperative variables between patients with normal and impaired liver function, mean ± SD/n (%).

	NL group (n = 27)	IL group (n = 29)	P value
Age (years), median (IQR)	66 (60-74)	71 (68-77)	0.034a
Sex (men/women)	15 (55.6)/12 (44.4)	22 (75.9)/7 (24.1)	0.109
Indication of liver resection			0.003b
Colorectal liver metastasis	16 (59.3)	9 (31.0)
Hepatocellular carcinoma	3 (11.1)	17 (55.6)
Biliary tract cancer	4 (14.8)	1 (3.5)
Others	4 (14.8)	2 (6.9)
Indocyanine green retention rate at 15 minutes (%), median (IQR)	7.2 (6.2-7.8)	14.1 (11.7-18.8)	< 0.001b
Kinetic indocyanine green elimination rate constant, median (IQR)	0.175 (0.170-0.186)	0.131 (0.111-0.143)	< 0.001b
Fibrosis-4 index, median (IQR)	1.46 (1.13-2.38)	2.48 (1.37-4.35)	0.014a
Albumin-bilirubin scoring	-2.69 ± 0.08	-2.49 ± 0.08	0.082
Modified ALBI grade (1/2a/2b)	15 (55.6)/10 (37.0)/2 (7.4)	11(37.9)/8 (27.6)/10 (34.5)	0.047a
Number of complete resected Couinaud segments, median (IQR)	1 (0-2)	0 (0-2)	0.419
Laparoscopic surgery	10 (37.0)	12 (41.1)	0.740
Extrahepatic bile duct resection	2 (7.4)	2 (6.9)	0.941
Concomitant colorectal resection	2 (7.4)	1 (3.5)	0.511
Operative duration (minute), median (IQR)	297 (218-328)	288 (224-384)	0.850
Intraoperative blood loss (mL), median (IQR)	388 (100-641)	290 (83.5-523)	0.774
Intraoperative red blood cell transfusion	5 (18.5)	6 (20.7)	0.838
Intraoperative fluid balance (mL/kg/hour), median (IQR)	8.1 (6.4-12.0)	8.2 (6.6-12.4)	0.844
Preoperative body weight (kg), median (IQR)	57.7 (51.9-71.8)	59.7 (53.3-64.2)	1.000
Maximum postoperative weight gain (%), median (IQR)	2.4 (1.0-6.1)	3.1 (1.5-7.5)	0.403
Complications (Clavien-Dindo grade ≥ IIIa) (%)	4 (14.8)	8 (27.6)	0.245

^aP < 0.05.

^bP < 0.01.

Statistical analyses: Mann-Whitney U test for continuous variables, χ² or Fisher exact test for categorical variables. For normal liver group: Indocyanine green retention rate at 15 minutes (ICG_R15) < 10%, and for impaired liver group: ICG_R15 ≥ 10%. NL: Normal liver; IL: Impaired liver; IQR: Interquartile range; ALBI: Albumin-bilirubin.

Comparison by surgical extent

When comparing the surgical procedures, there were no significant differences in age, sex, preoperative body weight, or liver function indices. The MajLR group had a significantly longer operative time and greater blood loss. In addition, biliary tract cancer requiring extrahepatic bile duct resection was more frequently observed in this group. Although the difference was not statistically significant, the intraoperative water balance per unit body weight per hour was generally lower in the MajLR group (Table 3). Rates of body weight change and urine output were comparable between the two groups; however, drain output was significantly higher in the MajLR group: POD 1 [5.1 mL/kg (2.3-7.1 mL/kg) vs 2.0 mL/kg (1.2-3.6 mL/kg) body weight, P = 0.004], POD 2 [2.9 mL/kg (0.9-6.8 mL/kg) vs 1.2 mL/kg (0.6-2.6 mL/kg) body weight, P = 0.055], and POD 3 [3.8 mL/kg (1.3-11.7 mL/kg) vs 0.8 mL/kg (0.4-1.9 mL/kg) body weight, P = 0.005]. PAC was higher in the MinLR group than in the MajLR group immediately after surgery [101.2 pg/mL (81.7-132.2 pg/mL) vs 78.2 pg/mL (54.5-100.6 pg/mL), P = 0.037], but this difference disappeared by POD 1 and did not reappear thereafter. Both groups showed peaks in AVP immediately after surgery, with no difference between them at that time; however, on POD 1, AVP was significantly higher in the MajLR group [10.1 pg/mL (5.4-15.7 pg/mL) vs 4.9 pg/mL (2.6-9.8 pg/mL), P = 0.036] (Figure 3). From POD 2 onward, AVP gradually decreased in both groups, with no significant group differences. When AVP ≥ 4.0 pg/mL was defined as hypervasopressinemia, its occurrence was significantly more frequent in the MajLR group on POD 1 (91% vs 58% in the MinLR group, P = 0.04), and this trend persisted on POD 5 (27% vs 7%, P = 0.05) (Figure 4). There was no difference in this tendency based on the surgical approach (laparoscopic or open).

Figure 3 Comparison of plasma aldosterone concentration and arginine vasopressin dynamics by surgical extent. A and B: Changes in plasma aldosterone concentration (PAC) (A) and arginine vasopressin (AVP) (B) in major liver resection (MajLR) (orange line) and minor liver resection (MinLR) (green line) groups. PAC transiently increased immediately after liver resection in both groups, whereas AVP elevation persisted longer in MajLR cases. AVP levels on postoperative day 1 were significantly higher in MajLR than in MinLR. Values are expressed as medians with interquartile ranges. ^aP < 0.05. MinLR: Minor liver resection; MajLR: Major liver resection; PAC: Plasma aldosterone concentration; AVP: Arginine vasopressin; LR: Liver resection; POD: Postoperative day.

Figure 4 Incidence of hypervasopressinemia after liver resection according to surgical extent. The major liver resection (MajLR) group (orange bars) had a higher proportion of patients with plasma arginine vasopressin ≥ 4.0 pg/mL compared to the minor liver resection group (green bars). Hypervasopressinemia was significantly more frequent in the MajLR group on postoperative day (POD) 1 and 5. Although the early increase on POD 1 likely reflects intraoperative fluid-restrictive management and hemodynamic shifts inherent to major liver resection, the persistence to POD 5 despite postoperative rehydration suggests a prolonged neuroendocrine response proportional to surgical stress. ^aP < 0.05. MinLR: Minor liver resection; MajLR: Major liver resection; LR: Liver resection; POD: Postoperative day.

Table 3 Comparison of perioperative variables between patients undergoing minor and major liver resection, n (%).

	MinLR group (n = 45)	MajLR group (n = 11)	P value
Age (years), median (IQR)	69 (65-75)	69 (64-77)	0.942
Sex (men/women)	31 (68.9)/14 (31.1)	6 (54.6)/5 (45.5)	0.368
Indication of liver resection			0.053
Colorectal liver metastasis	23 (51.1)	2 (18.2)
Hepatocellular carcinoma	15 (33.3)	5 (45.5)
Biliary tract cancer	2 (4.4)	3 (27.3)
Others	5 (11.1)	1 (9.1)
Indocyanine green retention rate at 15 minutes (%), median (IQR)	10.0 (7.4-17.2)	10.4 (6.2-14.1)	0.458
Kinetic indocyanine green elimination rate constant, median (IQR)	0.155 (0.118-0.173)	0.165 (0.131-0.186)	0.265
Number of complete resected Couinaud segments, median (IQR)	0 (0-1)	3 (3-4)	< 0.001b
Laparoscopic surgery	19 (42.2)	3 (27.3)	0.363
Extrahepatic bile duct resection	0 (0.0)	4 (36.4)	< 0.001b
Concomitant colorectal resection	3 (6.7)	0 (0.0)	0.379
Operative duration (minute), median (IQR)	278 (207-337)	382 (301-665)	0.002b
Intraoperative blood loss (mL), median (IQR)	290 (67-484)	1124 (150-2188)	0.015a
Intraoperative red blood cell transfusion	7 (15.6)	4 (36.4)	0.119
Intraoperative fluid balance (mL/kg/hour), median (IQR)	8.9 (6.8-12.5)	6.9 (4.5-8.8)	0.058
Preoperative body weight (kg), median (IQR)	58.1 (52.2-68.0)	59.7 (54.0-65.0)	0.845
Maximum postoperative weight gain (%), median (IQR)	2.6 (1.2-6.3)	3.5 (1.0-6.4)	0.918
Complications (Clavien-Dindo grade ≥ IIIa) (%)	6 (13.3)	6 (54.6)	0.003b

^aP < 0.05.

^bP < 0.01.

Statistical analyses: Mann-Whitney U test for continuous variables, χ² or Fisher’s exact test for categorical variables. Minor liver resection < 3 Couinaud segments, major liver resection ≥ 3 Couinaud segments (Brisbane 2000 classification). MinLR: Minor liver resection; MajLR: Major liver resection; IQR: Interquartile range.

In summary, PAC rose transiently from immediately after surgery to POD 1 and normalized by POD 2, whereas AVP remained elevated until at least POD 3; the prevalence of AVP ≥ 4.0 pg/mL was significantly higher after MajLR. In particular, MajLR was associated with prolonged elevation of AVP and a greater frequency of hypervasopressinemia, suggesting a role for AVP in fluid retention management. When hypervasopressinemia was observed on POD 1, urine output per kilogram of body weight was significantly lower on POD 1 (23.7 ± 1.5 mL/kg vs 32.0 ± 2.5 mL/kg body weight, P = 0.010) and POD 2 (30.3 ± 2.4 mL/kg vs 38.9 ± 3.2 mL/kg body weight, P = 0.036).

DISCUSSION

In this study, we observed the following findings after liver resection: (1) A transient increase in body weight, peaking at POD 2-3; (2) PAC levels that rose immediately after surgery and returned to baseline by POD 2; and (3) AVP levels that peaked immediately after surgery and remained elevated until at least POD 3, with a particularly high frequency of elevated vasopressin (AVP ≥ 4.0 pg/mL) in MajLR cases. Interestingly, patients who underwent MajLR had higher postoperative AVP levels despite appropriate fluid replacement in the ICU. During liver resection, intraoperative fluid infusion is intentionally restricted as part of a low central venous pressure strategy to minimize hepatic venous bleeding[23-25], which transiently reduces effective circulating volume and may stimulate AVP secretion. In addition, a longer operative time and greater surgical stress during MajLR may further enhance vasopressin release. The persistence of elevated AVP levels even after adequate postoperative rehydration suggests that the vasopressin response reflects not only transient hemodynamic changes but also the magnitude of surgical stress characteristic of MajLR. Although both AVP levels and the incidence of Clavien-Dindo grade ≥ IIIa complications were higher in the MajLR group, multiple confounding factors including surgical complexity, operative duration, and perioperative fluid shifts limit the ability to draw causal inferences. Nevertheless, these findings suggest that extensive liver resection is associated with a variety of physiological stimuli that can lead to elevated AVP levels. The surgical approach (laparoscopic vs open) did not affect the occurrence of postoperative hypervasopressinemia, suggesting that surgical invasiveness determined by the extent of resection is a more important factor.

The time course of these changes was consistent with decreases in urinary sodium, increases in drain output, and increases in body weight. These findings suggest that, in addition to the RAAS, the AVP axis contributes to early postoperative free water retention. The behavior of PAC aligns with previous reports of secondary aldosteronism associated with liver dysfunction[8,14] and with postoperative increases in PAC following liver resection[9]. Although augmentation of the RAAS due to postoperative decreases in effective circulating blood volume or sympathetic nervous activation is assumed to underlie these changes, PAC elevations in this study generally resolved by POD 2. This finding is interpreted as reflecting diminished RAAS stimulation accompanying the stabilization of postoperative circulation and related factors.

In contrast, AVP levels remained elevated until POD 3, even after their initial postoperative peak, and this pattern was more pronounced in MajLR cases. The sustained elevation of AVP may result not only from postoperative non-osmotic triggers (such as effective hypovolemia, inflammation, pain, nausea, and hemodynamic changes) but also from factors specific to liver resection: (1) Decreased metabolic clearance due to reduced liver parenchymal mass; (2) Relative deficiency of arterial blood volume caused by visceral vasodilation or bleeding after major resection; and (3) Hypothalamic pituitary axis stimulation induced by analgesics (opioids). In this study, both serum and urinary sodium levels reached their lowest points around POD 2, with body weight peaking at approximately the same time. These findings suggest augmented free water reabsorption via V2 receptor activation, consistent with the sustained elevation of AVP levels. Although reduced urine output in patients with elevated AVP is physiologically plausible, other factors including relative hypovolemia, visceral vasodilation, and the use of perioperative diuretics may also contribute and cannot be fully separated in this observational setting.

Spironolactone and canrenoic acid, administered to all patients as part of the standard postoperative protocols, competitively block aldosterone action by binding to its receptors in the distal renal tubules. Although these agents may exert a feedback effect on the RAAS and potentially influence postoperative PAC levels, they do not directly suppress aldosterone secretion. Therefore, an early increase in PAC cannot be fully attributed to the pharmacological effects of aldosterone antagonists. Notably, in the IL group, PAC remained elevated until POD 1, a pattern consistent with the well-described phenomenon of heightened RAAS reactivity in impaired livers. This suggests that the observed PAC response largely reflects physiological activation induced by surgical stress rather than solely medication-related effects. The divergence observed in this study specifically, that “PAC normalizes early, whereas AVP remains elevated until POD 3” may indicate that although sodium retention mediated by the RAAS is pharmacologically attenuated, free water reabsorption through the AVP axis relatively predominates. Nevertheless, because PAC declined even under anti-aldosterone therapy, these findings suggest that AVP plays a key role in postoperative water retention after liver resection. These hormonal changes were accompanied by clinical indicators of water retention, including postoperative weight gain, a decline in serum and urinary sodium around POD 2, and increased drain output after major resection. These findings parallel the sustained elevation of AVP, supporting the predominance of AVP-mediated free water retention in the early postoperative period. These mechanistic interpretations should be regarded as hypothesis-generating, as endocrine responses after liver resection are influenced by multiple perioperative factors.

Liver function analysis showed that an increase in PAC was evident immediately after liver resection until POD 2 in the IL group, whereas it was only present immediately after surgery in the NL group. Although the intergroup difference was not statistically significant, a trend was observed that supports previous findings of heightened RAA reactivity in damaged livers[9]. Analysis by surgical procedure revealed that the MajLR group exhibited greater drain output and significantly elevated AVP levels on POD 1, suggesting strong AVP activation in cases experiencing greater surgical stress. In our institution, intraoperative fluid management typically follows a low-central venous pressure strategy during hepatic transection to minimize bleeding; however, detailed hemodynamic targets were not strictly standardized and may have varied among cases. However, the higher proportion of patients with elevated AVP in the MajLR group supports the coexistence of excessive free water reabsorption and third-space fluid shifts. Clinically, these findings suggest that perioperative fluid management should not be guided solely by the RAAS; instead, the AVP axis should be considered from an early stage. Additionally, V2 receptor antagonists are now the standard therapy for refractory ascites in liver cirrhosis[26-28], and a postoperative weight gain exceeding 3.5 kg after liver resection is regarded as an independent risk factor for postoperative complications[6]. In other words, even when PAC decreases by POD 2, cases in which AVP remains high until approximately POD 3, as seen in MajLR, may not be adequately controlled by anti-aldosterone agents alone. The use of V2 receptor antagonists (tolvaptan) is rational in this context because these agents induce aquaresis (water excretion) without sodium loss. Among patients undergoing highly invasive procedures such as MajLR, particularly those showing tendencies toward weight gain or significant drain output, the early initiation of V2 receptor antagonists may merit consideration. However, because this study had an observational design, the validation of its efficacy and safety will require prospective interventional studies. Although the observed differences in hormonal activation and fluid retention are likely influenced by the magnitude of surgical stress, these findings nonetheless suggest that AVP activation contributes to postoperative water retention alongside the RAAS. Whether therapeutic interventions targeting these hormonal pathways can improve postoperative outcomes remains unclear; however, our findings provide fundamental evidence for future interventional studies. Although few studies have reported reductions in complications[29] and pleural effusion[30] following tolvaptan administration after liver resection, a phase I/II trial is planned to evaluate whether tolvaptan reduces postoperative ascites in patients with cirrhosis[31].

In Japan, diuretic therapy after liver resection has traditionally been guided by ICGR15, which remains a practical and widely accepted indicator when assessing hepatic functional reserve and determining postoperative fluid management strategies. Accordingly, patients in this study were stratified into NL and IL groups based on ICGR15, reflecting real-world clinical practice. Although ICGR15 was the primary indicator used for stratification, additional liver function parameters such as the FIB-4 index and the ALBI score were included to provide a more comprehensive characterization of baseline hepatic reserve. Notably, the IL group exhibited a significantly higher FIB-4 index and worse modified ALBI grade compared with the NL group, indicating that this ICGR15-based stratification was consistent with more advanced underlying liver injury. The concordance of these liver function markers supports the validity of the IL/NL grouping used in this study.

The strength of this study lies in the parallel measurement of PAC and AVP from the preoperative period to POD 5, according to a standardized protocol at a single institution, with stratified analyses based on liver function and surgical procedures. However, this study has some limitations: (1) It was a single-center, small-scale study with limited statistical power; (2) No corrections were applied for multiple comparisons in the exploratory analyses. This approach was considered acceptable given the hypothesis-generating nature of the hormonal time-course evaluation; (3) Measurement of AVP has inherent pre-analytical limitations. AVP is unstable because of its short half-life and susceptibility to degradation during sample handling, and thus absolute values obtained by RIA should be interpreted with caution. Nevertheless, all samples were processed under strictly uniform conditions using the same pre-analytical procedures and RIA platform, ensuring consistency across time points; (4) Several covariates including fluid balance, analgesic methods, opioid use, and osmolality were insufficiently controlled. In particular, perioperative opioid dosage was not uniformly documented, limiting the assessment of its potential effect on AVP secretion. Baseline tumor pathology (e.g., HCC vs CRLM) may also influence surgical stress and endocrine responses, although the study was not powered to adjust for these differences; (5) The use of RAAS-related medications and diuretics varied according to real-world clinical practice. Although these agents may have influenced the absolute values of PAC or AVP, this study focused on the temporal changes in hormonal dynamics rather than cross-sectional comparisons. Therefore, although their potential effects cannot be completely excluded, they are unlikely to have materially altered the interpretation of the characteristic postoperative patterns observed; (6) Clinical outcomes, including surgical site infection and respiratory complications, were not directly examined; and (7) Finally, correlations between AVP levels and postoperative complications could not be assessed because of the limited number of events. Although postoperative weight gain > 3.5 kg has been reported as a predictor of complications[6], the number of events in this cohort was insufficient for a meaningful analysis.

Nevertheless, no systematic reports have examined the postoperative course of AVP after liver resection, and we believe that this study provides important foundational data for developing future strategies regarding diuretic use after liver resection. Patients with persistent AVP elevation, particularly those undergoing MajLR, also demonstrated lower urine output and greater drain output, both of which clinically reflect increased third-space fluid accumulation. These findings suggest that V2 receptor antagonists may be beneficial in cases with early postoperative hypervasopressinemia. Optimal perioperative fluid management algorithms are expected to be established through prospective trials that investigate risk stratification based on surgical method and hormone levels, as well as the early introduction of V2 receptor antagonists in high-risk patients undergoing liver resection.

CONCLUSION

Both PAC and AVP levels increased after liver resection. However, PAC showed a transient fluctuation limited to the immediate postoperative period through POD 1, whereas AVP remained elevated until POD 3, with elevations particularly frequent after MajLR. These observational findings provide fundamental data on postoperative hormonal regulation and may serve as a basis for future investigations evaluating AVP-targeted (V2) therapeutic strategies.

ACKNOWLEDGEMENTS

We thank BML Inc., for the hormone assays. BML was not involved in the study design, analysis, interpretation, or decision to submit the manuscript.