Cirrhosis represents a major global health burden, with ascites being one of its most common complications, affecting approximately 60% of patients within 10 years of diagnosis[1]. Hepatorenal syndrome (HRS), a functional renal failure occurring in advanced cirrhosis, is a dire complication with high mortality. It arises from severe circulatory dysfunction characterized by splanchnic vasodilation, reduced effective arterial blood volume, and subsequent renal vasoconstriction[1-3]. Portal hypertension is a prerequisite for ascites formation, driven by increased hepatic vascular resistance and portal venous inflow[2]. The progression to HRS involves activation of vasoconstrictor systems (renin-angiotensin-aldosterone and sympathetic nervous systems) and impaired renal autoregulation[3,4].

The incidence of HRS in cirrhotic patients with ascites is alarmingly high. Studies report a 1-year probability of 18–23.6%, escalating to 39% at 5 years[5-7]. Spontaneous bacterial peritonitis (SBP), gastrointestinal bleeding, and large-volume paracentesis without albumin are key precipitants[1]. Once established, HRS carries a median survival of just two weeks without intervention[4].

Prognostic markers for HRS development and outcomes are critical for risk stratification. Independent predictors include:

• Hyponatremia (serum sodium <135 mmol/L)[3,6]
• Elevated plasma renin activity[6]
• Absence of hepatomegaly[6]
• History of ascites (adjusted OR: 5.8, 95% CI: 2.6–13.0)[8,9]
• Bilirubin >2 mg/dL (strongest predictor: OR 9.5, 95% CI: 5.1–17.7)[3,8]
• Albumin <2–3 g/dL (OR 3.9, 95% CI: 1.1–13.5)[8,9]
• Serum creatinine >2.5 mg/dL (OR 2.5, 95% CI: 1.2–5.5)[8,9]
• Spontaneous bacterial peritonitis (OR 5.5, 95% CI: 1.4–12.2)[8,9]

Mortality correlates with biochemical markers like bilirubin, creatinine, and albumin[10,11]. Child-Pugh score, however, does not independently predict HRS[6]. Early diagnosis using acute kidney injury (AKI) criteria facilitates prompt treatment, though liver transplantation remains the only definitive therapy[1,4].

Despite established diagnostic criteria (International Ascites Club), gaps persist in risk stratification within diverse tertiary care populations. Most predictive models derive from Western cohorts, warranting validation in multiethnic settings. Additionally, the interplay between novel biomarkers (e.g., endothelin-1) and clinical predictors remains underexplored[2,4]. This study aims to address these gaps by analyzing the incidence and prognostic markers of HRS in cirrhotic patients with ascites at a tertiary care center, enhancing early intervention strategies.

Study Design and Setting-This prospective observational study was conducted at the Department of Medicine, MGM College & MY Hospital, Indore, from 1st March 2023 to 31st March 2024. A total of 100 consecutive patients who met the inclusion criteria were recruited from the outpatient department (OPD), Medical Intensive Care Unit (MICU), and medicine wards of the hospital.

Study Population-The study included 100 cirrhotic patients with ascites who were admitted to the hospital during the study period. These patients were diagnosed with cirrhosis based on clinical or histological evidence, irrespective of the etiology of the cirrhosis.

Inclusion Criteria

1. Patients with ascites.
2. Clinical or previous histological diagnosis of liver cirrhosis, regardless of etiology.
3. Absence of gastrointestinal hemorrhage within one month prior to admission.
4. Absence of hepatic encephalopathy or bacterial infection at the time of study.
5. No other apparent cause for acute kidney injury, including shock, nephrotoxic drug use, or ultrasonographic evidence of obstruction or parenchymal kidney disease.

Exclusion Criteria

• Patients not providing consent.
• Pregnant females, prisoners, or psychiatric patients.
• Renal failure (GFR < 50 ml/min), or any clinical, laboratory, or echocardiographic evidence of respiratory, cardiac, or renal diseases.
• Patients with hepatic encephalopathy or symptoms suggestive of bacterial infection at the time of study enrollment.

Sample Size Calculation-The sample size was calculated using G*Power software version 3.1.9.2. Based on a 95% confidence interval and 90% power, a final sample size of 100 patients was determined using convenient sampling.

Study Duration-The study was carried out over a period of 12 months, from 1st March 2023 to 31st March 2024.

Data Collection-Data were collected using a pre-tested and pre-validated proforma after obtaining written informed consent from each patient. The following data were recorded:

• Demographic Information: Age, sex, place of residence (urban/rural), religion, etc.
• Medical History: Presenting complaints, history of chronic medical, psychiatric, and surgical illnesses, history of drug treatments, family history of chronic conditions, and personal history (dietary habits, sleep patterns, bowel and bladder function, substance abuse).
• Clinical Examination: General examination including vitals (blood pressure, heart rate, temperature, and respiratory rate), systemic examination, and mean arterial pressure (calculated at baseline and follow-up).

Investigations

• Routine Laboratory Investigations: Complete blood count, blood urea nitrogen, serum creatinine, serum sodium, serum potassium, ascitic fluid routine and microscopy, and urine routine and microscopy.
• Additional Investigations: Upper gastrointestinal endoscopy and abdominal ultrasonography (USG).
• Follow-up Investigations: At every 3-month interval, complete hemogram, renal function tests, liver function tests, urine routine and microscopy, urinary spot sodium, and ascitic fluid analysis.
• Investigations in Suspected HRS: In patients suspected of HRS, investigations included complete hemogram, renal function tests, liver function tests, urine routine and microscopy, urinary spot sodium, ascitic fluid analysis, and stool examination for occult blood.

Hepatorenal Syndrome (HRS) Diagnosis-HRS was classified according to the International Club of Ascites (ICA) consensus guidelines. HRS was divided into two subtypes:

• HRS-AKI (Acute Kidney Injury): Defined by an acute increase in serum creatinine of ≥0.3 mg/dl within 48 hours, or urinary output <0.5 ml/kg for >6 hours, or an increase in serum creatinine of ≥50% from a stable baseline within the previous 3 months.
• HRS-NAKI (Non-Acute Kidney Injury): Diagnosis was made based on clinical criteria and exclusion of other causes of renal impairment.

Liver Disease Severity Assessment-The Child-Pugh score was calculated for each patient using the five parameters: serum bilirubin, serum albumin, international normalized ratio (INR), ascites, and encephalopathy.

Statistical Analysis-Data were entered and cleaned using MS Excel and analyzed statistically using SPSS version 25. Quantitative variables were expressed as mean ± standard deviation or median ± interquartile range. Qualitative data were expressed as percentages. The association between variables was assessed using appropriate statistical tests, with a p-value <0.05 considered statistically significant.

Ethical Considerations-The study protocol was presented to the institutional ethical committee for approval. Following approval, written informed consent was obtained from all participants or their legally acceptable representatives before enrollment. The study adhered to ethical principles in line with the Declaration of Helsinki.

Table 1: Patient Demographics and Clinical Characteristics (N=100)

This table provides an overview of the baseline demographics and clinical features of the 100 cirrhotic patients included in the study. A predominant male representation (82%) was observed, with only 18% being female. The majority of patients fell within the 31–45 years (47%) and 46–60 years (41%) age groups, indicating that middle-aged adults were most commonly affected. Regarding the etiology of liver disease, alcohol-related cirrhosis was the leading cause (58%), followed by cryptogenic (16%), autoimmune (14%), and viral hepatitis (12%). When evaluated via upper GI endoscopy, most patients (67%) had Grade 2 esophageal varices, showing a high burden of portal hypertension complications.

Table 2: Incidence and Outcomes of Hepatorenal Syndrome

This table highlights both the incidence of hepatorenal syndrome (HRS) and the final clinical outcomes. HRS was diagnosed in 17% of the study population, while 83% did not develop it. Mortality analysis revealed that 17 patients (17%) died during the study, 77% survived, and 6% were lost to follow-up. These data underscore a significant mortality burden associated with HRS among cirrhotic patients.

Table 3: Prognostic Laboratory and Clinical Parameters

*Statistically significant (p<0.05)

This table compares key laboratory and hemodynamic parameters at admission versus at the point of HRS diagnosis. Statistically significant differences were noted in all parameters except SAAG. HRS diagnosis was marked by a steep rise in serum creatinine and potassium, along with a notable decline in urine output, serum sodium, and mean arterial pressure. The Child-Pugh score also increased significantly, reflecting worsening hepatic function. These trends highlight the sharp deterioration in renal and systemic physiology associated with HRS onset.

Table 4: Clinical Complications and Precipitating Factors for HRS

This table outlines complications and possible triggers linked with HRS among the affected patients. Upper GI bleeding (58.8%), spontaneous bacterial peritonitis (52.9%), and hepatic encephalopathy (35.3%) were the most common precipitating factors. A majority (70.6%) had a single identifiable trigger, whereas 29.4% had multiple concurrent complications. These findings emphasize the role of acute events in precipitating HRS in vulnerable cirrhotic individuals.

Table 5: HRS-Related Mortality

This table focuses on the mortality implications of developing HRS. Of the 17 patients diagnosed with HRS, 13 died—translating to a high mortality rate of 76.5% within this subgroup. In contrast, mortality in non-HRS patients was significantly lower (4.8%). HRS accounted for the majority of deaths in the overall cohort, reaffirming its role as a critical and often fatal complication in cirrhotic patients.

Table 6: Age-Specific HRS Incidence

This table evaluates the distribution of HRS cases across different age groups. The highest incidence of HRS was seen in patients aged 46–60 years (29.3%), followed by those older than 60 years (20%). The 31–45 years age group showed an 8.5% incidence, while no HRS cases were reported among patients aged 18–30. This age-stratified data suggests that advancing age, particularly beyond 45 years, is associated with a higher risk for HRS development.

The study's finding of 82% male predominance aligns closely with established literature patterns. Multiple studies have consistently reported male predominance in HRS, with rates ranging from 67% to 76%[12,13]. A recent clinical profile study of 100 HRS patients found 76% were male[12], while another investigation reported 67% male patients[14]. This gender distribution reflects the higher prevalence of alcohol-related liver disease among males and the increased likelihood of alcohol consumption leading to cirrhosis in this demographic[12,15].The study's age distribution findings align with international literature, showing HRS predominantly affects middle-aged adults. The concentration of cases in the 31-45 years (47%) and 46-60 years (41%) age groups is consistent with studies reporting mean ages between 46.3-61.3 years[12]. Madagascar-based research noted that the cirrhotic population is relatively young compared to European populations, with clear male predominance (83%) and sex ratio of 4.9[15]. The absence of HRS cases in the 18-30 years age group supports literature suggesting older age as a significant risk factor for HRS development[16].The study's finding of 58% alcohol-related cirrhosis is consistent with global patterns, though shows regional variation. Literature reports alcohol as the most common HRS etiology, with studies showing alcoholic cirrhosis accounting for 46.3% to 78% of cases[12,15]. A large US study found that over one-third (36%) of cirrhosis cases are alcohol-related[17]. The predominance of alcohol-related etiology underscores the global impact of alcohol use disorder on liver disease development and subsequent HRS risk.The study's HRS incidence of 17% falls within the higher range of reported rates in hospitalized cirrhotic patients. Literature shows considerable variation in HRS incidence: hospitalized patients with cirrhosis and ascites show rates of 8-20% annually, with some studies reporting 10% among hospitalized patients with cirrhosis and ascites[18]. A Turkish study using current diagnostic criteria found 12.7% HRS incidence[19], while other investigations report rates ranging from 7.5% to 10.3%[19,20]. The study's 17% incidence suggests either a sicker patient population or differences in diagnostic criteria application.The study's mortality findings reveal both concerning and encouraging aspects when compared to literature. The overall cohort mortality of 17% with 76.5% of deaths occurring in HRS patients demonstrates the severe prognosis associated with this condition. This aligns with literature showing HRS mortality rates ranging from 32% to 85% at three months[21,22]. Studies report median survival of 2 weeks for HRS-AKI without treatment[18], while 90-day mortality ranges from 35% for prerenal azotemia to 57-58% for HRS and acute tubular necrosis[23]. The study's finding of 84.3% survival rate in non-HRS patients is more favorable than some literature reports.The study's identification of key prognostic factors aligns well with established literature. Elevated serum creatinine, decreased urine output, hyponatremia, reduced mean arterial pressure, and increased Child-Pugh scores are consistently reported as significant predictors[24,25]. Literature confirms that patients with HRS typically have advanced liver disease (median Child-Pugh score 11.2), low mean arterial pressure (median 74 mmHg), and hyponatremia (median serum sodium 127 mEq/L)[25]. Studies consistently identify hyponatremia (<135 mEq/L), hypoalbuminemia (<2.45 g/dL), and elevated MELD scores as significant risk factors[24].The study's findings on precipitating factors show strong concordance with literature. Upper gastrointestinal bleeding (58.8%) and spontaneous bacterial peritonitis (52.9%) as primary triggers align with established patterns. Literature consistently identifies infection (48% of patients), GI bleeding (33%), and large-volume paracentesis (27%) as the most common precipitating factors[14]. Spontaneous bacterial peritonitis affects approximately one-third of patients with cirrhosis and ascites, leading to renal failure[20]. The finding of 29.4% having multiple concurrent complications reflects the complex pathophysiology of HRS development.The study's finding of 67% Grade 2 esophageal varices reflects severe portal hypertension in the study population. Literature indicates that esophageal varices are detected in about 50% of cirrhosis patients[21], with up to 90% of cirrhotic patients eventually developing varices[22]. The high prevalence of Grade 2 varices suggests an advanced cirrhotic population with significant portal hypertension, which correlates with increased HRS risk.The study's age-stratified analysis showing highest HRS rates in 46-60 years (29.3%) and >60 years (20%) age groups confirms age as a significant risk factor. This finding aligns with literature demonstrating that older adults are at higher risk due to natural decline in kidney function with age[16]. The absence of HRS in the youngest age group (18-30 years) supports the concept that HRS predominantly affects middle-aged and older adults with advanced liver disease.

This study highlights that hepatorenal syndrome (HRS) remains a significant and life-threatening complication among cirrhotic patients, particularly those in the middle-aged and older adult groups with alcohol-related liver disease. The high mortality rate associated with HRS underscores the need for early identification and management of key prognostic markers such as rising serum creatinine, hyponatremia, and declining mean arterial pressure. Precipitating factors like spontaneous bacterial peritonitis and gastrointestinal bleeding play a crucial role in HRS development. Focused monitoring and timely intervention are essential to improve outcomes and reduce the burden of HRS in cirrhotic populations.

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