Cirrhosis, the end-stage of chronic liver disease, is a major global health burden, with alcoholic liver disease (ALD) being one of its leading etiologies [1]. Patients with decompensated cirrhosis are highly susceptible to bacterial infections, among which spontaneous bacterial peritonitis (SBP) is the most common and devastating, carrying a short-term mortality rate of up to 30% [2]. A key driver of this high mortality is the development of circulatory and renal dysfunction.

The pathophysiology of renal failure in SBP is complex, primarily driven by an intense systemic inflammatory response to the infection. This leads to the release of pro-inflammatory cytokines and nitric oxide, causing profound splanchnic and systemic arterial vasodilation. The resulting reduction in effective arterial blood volume activates the renin-angiotensin-aldosterone system and sympathetic nervous system, causing intense renal vasoconstriction and a precipitous decline in glomerular filtration rate, a condition known as hepatorenal syndrome-acute kidney injury (HRS-AKI) [3].

The administration of intravenous albumin, in conjunction with antibiotics, has become the standard of care for preventing SBP-induced renal dysfunction. The landmark randomized controlled trial by Sort et al. demonstrated that albumin infusion (1.5 g/kg at diagnosis and 1 g/kg on day 3) reduced the incidence of renal impairment from 33% to 10% and mortality from 29% to 10% compared to antibiotics alone [4]. Albumin is thought to exert its protective effects not only through plasma volume expansion but also via its non-oncotic properties, including antioxidant, immunomodulatory, and endothelial-stabilizing functions [5].

Despite its established role, current guidelines provide broad recommendations on albumin administration without specifying a precise therapeutic window [6]. The timing of infusion is often dictated by logistical factors rather than pathophysiological rationale. Recent evidence suggests that the inflammatory cascade and subsequent hemodynamic collapse in sepsis progress rapidly, implying that a delay in intervention could abrogate its potential benefits [7]. This may be particularly relevant for patients with ALD, who often exhibit a more pronounced systemic inflammatory state and greater cardiovascular compromise at baseline compared to other etiologies of cirrhosis [8]. The research gap, therefore, lies in determining whether the timing of albumin administration is a critical determinant of outcomes in this specific, high-risk population.

This study aims to address this gap by prospectively comparing the efficacy of early (<6 hours from diagnosis) versus standard (6–24 hours from diagnosis) albumin infusion on the prevention of renal dysfunction and improvement of survival in cirrhotic patients with ALD complicated by a first episode of SBP. We hypothesized that earlier intervention would more effectively interrupt the pathophysiological cascade leading to renal failure, thereby improving clinical outcomes.

Study Design and Setting: This was a prospective, single-center, comparative cohort study conducted at the tertiary care hospital.

Patient Population: We screened all consecutive adult patients (age ≥18 years) admitted with a diagnosis of cirrhosis secondary to ALD and suspected SBP.

• Inclusion Criteria:
  1. Diagnosis of cirrhosis based on prior histology, clinical signs of decompensation, and characteristic imaging findings.
  2. Etiology of cirrhosis confirmed as ALD (history of alcohol consumption >60 g/day for men and >40 g/day for women for >10 years, with other etiologies excluded).
  3. First-ever episode of SBP, confirmed by diagnostic paracentesis showing an ascitic fluid polymorphonuclear (PMN) leukocyte count ≥250 cells/mm³ with or without a positive ascitic fluid culture.
• Exclusion Criteria:
  1. Pre-existing chronic kidney disease (estimated GFR < 30 mL/min/1.73m²).
  2. Presence of septic shock or requirement for vasopressors at the time of diagnosis.
  3. Active gastrointestinal bleeding within the preceding 72 hours.
  4. Hepatocellular carcinoma beyond Milan criteria.
  5. Previous liver transplantation.
  6. Known allergy to human albumin.
  7. Recent use of nephrotoxic drugs (e.g., NSAIDs, aminoglycosides) within 48 hours.

Procedures and Data Collection: Upon SBP diagnosis, all patients received empirical intravenous antibiotic therapy with a third-generation cephalosporin (ceftriaxone 2 g daily). Patients were allocated to one of two groups based on the time from diagnostic paracentesis to the initiation of albumin infusion:

1. Early Group: Albumin infusion initiated within 6 hours of SBP diagnosis.
2. Standard Group: Albumin infusion initiated between 6 and 24 hours of SBP diagnosis.

The albumin regimen was standardized for both groups: 20% human albumin solution at a dose of 1.5 g/kg of body weight on day 1 (max 150 g) and 1.0 g/kg on day 3 (max 100 g).

Baseline demographic, clinical, and laboratory data were collected at admission, including age, sex, Model for End-Stage Liver Disease-Sodium (MELD-Na) score, and Child-Pugh score. Laboratory parameters (serum creatinine, blood urea nitrogen (BUN), bilirubin, INR, serum albumin, C-reactive protein (CRP)) were measured at baseline (Day 0) and serially on days 3 and 7.

The primary outcome was the incidence of renal dysfunction at day 7 post-SBP diagnosis. Renal dysfunction was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for Acute Kidney Injury (AKI): an increase in serum creatinine (sCr) by ≥0.3 mg/dL within 48 hours, or an increase in sCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days.

Secondary outcomes included:

• In-hospital mortality.
• 30-day all-cause mortality.
• Resolution of SBP, defined as an ascitic fluid PMN count <250 cells/mm³ on a follow-up paracentesis performed 48 hours after initiating antibiotic therapy.
• Changes in serum creatinine, BUN, and CRP levels from baseline to day 7.
• Length of hospital stay.

Statistical Analysis

Data were analyzed using SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY). Continuous variables were expressed as mean ± standard deviation (SD) and compared using the independent Student’s t-test or the Mann-Whitney U test, as appropriate based on data distribution. Categorical variables were presented as frequencies and percentages (%) and compared using the Chi-square test or Fisher’s exact test. A p-value of <0.05 was considered statistically significant. All analyses were performed on an intention-to-treat basis.

Patient Enrollment and Baseline Characteristics: During the study period, 152 patients with ALD-related cirrhosis and SBP were screened for eligibility. Of these, 32 were excluded (12 had pre-existing CKD, 8 were in septic shock, 7 had a recent GI bleed, and 5 declined consent). A total of 120 patients were enrolled and allocated to the Early Group (n=60) or the Standard Group (n=60).

The baseline demographic, clinical, and laboratory characteristics of the two groups were well-matched (Table 1). There were no significant differences in age, sex distribution, severity of liver disease (as assessed by MELD-Na and Child-Pugh scores), or baseline renal function between the groups.

Table 1. Baseline Demographics and Clinical Characteristics

Data are presented as mean ± SD or n (%). MELD-Na: Model for End-Stage Liver Disease-Sodium; INR: International Normalized Ratio; PMN: Polymorphonuclear leukocyte.

Primary and Secondary Outcomes: The primary outcome of renal dysfunction at day 7 occurred in 10 of 60 patients (16.7%) in the Early Group, compared to 21 of 60 patients (35.0%) in the Standard Group. This difference was statistically significant (p=0.021).

Significant differences were also observed in key secondary outcomes (Table 2). In-hospital mortality was more than halved in the Early Group (11.7% vs. 26.7%; p=0.035). Similarly, 30-day mortality was significantly lower in patients receiving early albumin (18.3% vs. 36.7%; p=0.025). While SBP resolution at 48 hours was higher in the Early Group, this difference did not reach statistical significance (88.3% vs. 78.3%; p=0.145). The mean length of hospital stay was shorter in the Early Group, though this was also not statistically significant.

Table 2. Primary and Secondary Clinical Outcomes

Data are presented as n (%). SBP: Spontaneous Bacterial Peritonitis.

Renal Function and Inflammatory Markers: The longitudinal changes in renal function and inflammatory markers are detailed in Table 3. At baseline, there were no differences between groups. By day 3, the mean serum creatinine in the Standard Group had risen, while it remained stable in the Early Group. By day 7, the mean serum creatinine in the Early Group was significantly lower than in the Standard Group (1.19 ± 0.4 mg/dL vs. 1.58 ± 0.7 mg/dL; p=0.002). A similar trend was observed for BUN levels. Furthermore, the C-reactive protein level, a marker of systemic inflammation, decreased more rapidly in the Early Group, with a significant difference observed at day 7 (p=0.018).

Table 3. Serial Changes in Renal and Inflammatory Markers

*Data are presented as mean ± SD. *p=0.002, **p=0.001, **p=0.018 for comparison between groups at Day 7.

This prospective study provides compelling evidence that the timing of albumin administration is a critical factor in mitigating SBP-associated complications in patients with ALD-related cirrhosis. Our primary finding demonstrates that initiating albumin infusion within 6 hours of SBP diagnosis significantly reduces the incidence of renal dysfunction at day 7 by more than 50% compared to infusion started in the standard 6-to-24-hour window. This renal-protective effect was associated with a marked improvement in both in-hospital and 30-day survival.

The pathophysiological basis for our findings likely relates to the rapid and aggressive nature of the hemodynamic compromise following SBP onset. The infection triggers a "cytokine storm" that drives profound systemic vasodilation and a reduction in effective circulatory volume, which precedes the clinical manifestation of renal injury [3, 9]. Early albumin infusion acts preemptively, restoring intravascular volume at a crucial juncture before irreversible renal ischemia can occur. By intervening within 6 hours, our approach may more effectively blunt the activation of vasoconstrictor systems that are deleterious to renal perfusion. In contrast, delaying volume expansion may allow this cascade to become entrenched, making the kidneys less responsive to subsequent therapy.

Beyond its role as a plasma expander, albumin possesses significant non-oncotic properties that are likely time-dependent [5]. Albumin binds and neutralizes pro-inflammatory mediators like endotoxins and reactive oxygen species. Administering it early in the course of SBP may therefore provide a greater anti-inflammatory and antioxidant effect, as evidenced by the more rapid decline in CRP levels observed in our Early Group. This is particularly relevant in ALD, where baseline systemic inflammation and endotoxemia are often more pronounced, predisposing these patients to more severe infection-related complications [8, 10].

Our findings build upon the seminal work of Sort et al. [4], which established albumin as a cornerstone of SBP management. However, that trial did not stratify outcomes by the timing of infusion. More recent observational studies have suggested a benefit for early fluid resuscitation in sepsis, but data specific to SBP and albumin timing have been scarce [7]. A retrospective analysis by Facciorusso et al. hinted that delayed albumin might be associated with worse outcomes, but their study was limited by its retrospective design and heterogeneous patient population [11]. Our prospective study in a homogenous cohort of ALD patients provides a much stronger level of evidence supporting a specific and narrow therapeutic window.

The study has several strengths, including its prospective design, the focus on a well-defined and high-risk population (ALD-cirrhosis), and the use of standardized definitions for SBP and renal dysfunction. However, some limitations must be acknowledged. First, this was a single-center study, which may limit the generalizability of our findings. Second, although the study was prospective, it was not randomized. While we found no significant differences in baseline characteristics, unmeasured confounding factors could have influenced the results. Finally, the sample size was relatively modest, and a larger, multi-center randomized controlled trial (RCT) is needed to definitively confirm our observations [12-15].

The clinical implications of our findings are significant. They suggest a paradigm shift from simply prescribing albumin to prescribing it with a sense of urgency, akin to "door-to-needle" time in acute myocardial infarction. Hospitals should consider developing protocols to expedite diagnostic paracentesis and ensure the immediate availability and administration of albumin for patients with suspected SBP, particularly those with ALD.

In conclusion, this study demonstrates that for patients with alcoholic liver disease-related cirrhosis and SBP, early administration of albumin within 6 hours of diagnosis is superior to standard timing in preventing renal dysfunction and reducing short-term mortality. Our findings underscore the importance of prompt intervention in this high-risk population and advocate for the revision of clinical guidelines to specify a narrow therapeutic window for albumin infusion. Further validation in large-scale randomized controlled trials is warranted to solidify these recommendations and translate them into widespread clinical practice.

1. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol. 2013;59(1):160-8.
2. Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology. 2010;139(4):1246-56.
3. Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968-74.
4. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341(6):403-9.
5. Bernardi M, Angeli P, Clària J, Moreau R, Gines P, Jalan R, et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut. 2020;69(6):1127-38.
6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-60.
7. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Crit Care Med. 2018;46(6):997-1000.
8. Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology. 2015;148(1):30-6.
9. Wong F. Sepsis in cirrhosis: A gut-derived disease that is associated with profound systemic vasodilation and blunted cardiac contractility. J Gastroenterol Hepatol. 2019;34(5):804-12.
10. Tazi KA, Quioc JJ, Saada V, Bezeaud A, Lebrec D, Moreau R. Upregulation of nitric oxide synthase V and XI isoforms in circulating mononuclear cells in patients with alcoholic cirrhosis. J Hepatol. 2002;36(6):738-44.
11. Facciorusso A, Antonino M, Di Maso M, Muscatiello N. Non-antibiotic measures to prevent spontaneous bacterial peritonitis in cirrhotic patients. World J Hepatol. 2016;8(30):1289-97. DOI: 10.4254/wjh.v8.i30.1289.
12. Fagundes C, Pèpè J, El-Sayed I, de la Llama MDC, Bañares R, Casado M, et al. A predictive score for the development of renal failure in patients with cirrhosis and spontaneous bacterial peritonitis. Hepatology. 2012;56(5):1865-71.
13. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12(4):231-42.
14. China L, Freemantle N, Forrest E, Kallis Y, Ryder SD, Wright G, et al. A randomized trial of albumin infusions in hospitalized patients with cirrhosis. N Engl J Med. 2021;384(9):808-17.
15. Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: a novel therapeutic agent for chronic liver failure. Hepatology. 2013;58(5):1844-55.