Diagnostic utility of systemic inflammatory markers for acute cholecystitis in hemodialysis patients with end-stage renal disease

Authors: Hilal Erinanc, Gulhan Kanat Unler, Oznur Kal, Aynur Yonar

Abstract

Diagnosing acute cholecystitis (AC) in patients with end-stage renal disease (ESRD) is challenging because chronic systemic inflammation and immune dysregulation may obscure acute inflammatory responses. Conventional inflammatory markers may therefore have limited diagnostic specificity in this population. This study aimed to evaluate the diagnostic utility of systemic inflammatory indices in ESRD patients undergoing cholecystectomy. This retrospective single-center study included 48 ESRD patients who underwent cholecystectomy either for clinically suspected AC (AC group, n = 31) or prophylactically prior to kidney transplantation (RT group, n = 17). Demographic characteristics and laboratory parameters were obtained from preoperative blood tests. Systemic inflammatory indices, including the neutrophil-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index (SIRI), and pan-immune-inflammation value (PIV), were calculated. Histopathological findings were used as the reference standard for confirming acute inflammation. Exploratory receiver operating characteristic curve analysis was performed to evaluate diagnostic performance and determine optimal cutoff values. Histopathological examination demonstrated neutrophilic infiltration consistent with acute inflammation in 30% of patients with clinically suspected AC. Compared with the RT group, patients with histopathologically confirmed acute inflammation had significantly higher neutrophil counts and PIV levels and lower serum albumin levels. In receiver operating characteristic analysis comparing histopathologically confirmed acute cases with RT controls, PIV showed the highest diagnostic accuracy (area under the curve [AUC] = 0.771), followed by C-reactive protein (AUC = 0.733) and SIRI (AUC = 0.732). Within the AC cohort, SIRI demonstrated the best discriminatory ability for differentiating acute from chronic inflammatory changes (AUC = 0.732). Optimal cutoff values differed substantially between analyses, with lower thresholds observed when acute cases were compared with RT controls and higher thresholds required within the AC cohort. Composite inflammatory indices, particularly SIRI and PIV, may provide additional information in identifying histopathologically confirmed acute inflammation in ESRD patients. However, given the limited sample size, these findings should be interpreted as exploratory and require validation in larger prospective studies.

1. Introduction

Patients with end-stage renal disease (ESRD) are at increased risk for abdominal infections, including acute cholecystitis (AC), owing to chronic systemic inflammation, uremia-associated immune dysfunction, and a high burden of comorbid conditions. Gallstone disease is more prevalent in patients receiving renal replacement therapy than in the general population.^[1–3]^ Consequently, prophylactic cholecystectomy is often considered in ESRD patients who are candidates for kidney transplantation to reduce postoperative morbidity during immunosuppressive therapy.^[4,5]^

The diagnosis of AC is traditionally based on a combination of clinical findings, laboratory markers such as leukocytosis and C-reactive protein (CRP), and imaging modalities, primarily ultrasonography.^[6]^ However, in ESRD patients, these diagnostic tools may be less reliable because of atypical inflammatory responses and persistent baseline inflammation. Multiple mechanisms, including oxidative stress, metabolic disturbances, recurrent infections, and alterations in gut microbiota, contribute to this chronic inflammatory milieu.^[7]^

Accurate and timely diagnosis of AC is essential for appropriate surgical decision-making, particularly in ESRD patients, in whom chronic systemic inflammation may obscure acute inflammatory processes. Delayed or unnecessary surgical intervention may increase perioperative risk, while missed acute inflammation may result in serious complications. Evidence suggests that early cholecystectomy, especially within 72 hours of symptom onset, is associated with improved outcomes, whereas delayed intervention is often linked to more complex surgical management and prolonged hospitalization.^[8]^

Recently, composite systemic inflammatory indices derived from routine complete blood count parameters – such as neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune-inflammation value (PIV) – have been proposed as potential markers of acute inflammatory activity in various clinical settings.^[9–11]^ Although these indices have shown promise in various inflammatory conditions, their diagnostic value in ESRD patients with suspected AC remains unclear. These indices integrate information from multiple immune cell populations and may better reflect the balance between pro-inflammatory and regulatory responses than single laboratory parameters.

Histopathological examination remains the reference standard for confirming acute inflammatory changes of the gallbladder, as it objectively identifies neutrophilic infiltration of the gallbladder wall. However, it is not always consistent with clinical or radiological findings. This discordance highlights the need for adjunctive biomarkers that may help bridge the gap between clinical suspicion and biological evidence of acute inflammation. The presence or absence of neutrophilic infiltration in gallbladder tissue may provide a more objective basis for evaluating the diagnostic performance of inflammatory indices.

This study aimed to compare systemic inflammatory indices between ESRD patients undergoing cholecystectomy for AC and those undergoing prophylactic surgery prior to kidney transplantation. By using histopathological findings as the reference standard, we also sought to assess the ability of these markers to distinguish true acute inflammation from chronic or non-acute disease in a population characterized by baseline inflammatory burden.

2. Materials and methods

2.1. Study design and patient population

2.1.1. Clinical case definition of AC

This retrospective, single-center study included ESRD patients who underwent cholecystectomy between January 2015 and December 2025. Eligible patients were receiving chronic dialysis and underwent surgery either for AC (AC group) or as a prophylactic procedure prior to kidney transplantation (RT group).

Data were collected from hospital archives and electronic patient records.

All AC group patients aged 18 years or older who were admitted with a diagnosis of acute calculous cholecystitis and subsequently evaluated by the General Surgery Department were included in the study.

Preoperative clinical suspicion of AC was established in accordance with the Tokyo Guidelines 2018 (TG18),^[6]^ based on a combination of clinical presentation, laboratory findings (including CRP and white blood cell [WBC] levels), and radiological imaging.

The clinical diagnosis relied on 3 local signs of inflammation, including Murphy sign or right upper quadrant pain, tenderness, or palpable mass; systemic signs of inflammation, such a fever, elevated CRP levels, or increased WBC count (leukocytosis); and characteristic imaging findings, including gallbladder wall thickening, gallbladder enlargement, gallstones, or pericholecystic fluid.

Disease severity was graded according to the Tokyo severity grading system as grade I (mild, without organ dysfunction), grade II (moderate, with marked local inflammation or symptom duration > 72 hours), or grade III (severe, associated with organ dysfunction involving the cardiovascular, respiratory, or renal systems).

Clinical variables such as demographic characteristics, right upper quadrant tenderness, presence of a positive Murphy sign, laboratory parameters, and imaging reports were systematically reviewed for findings consistent with AC according to the TG18.

Upon retrospective review of medical records, patients in the AC group fulfilled the TG18 criteria for the clinical diagnosis of AC, and the disease severity of cases was classified as mild.

Patients with concurrent systemic infection, autoimmune disease, active malignancy, ongoing immunosuppressive therapy, or incomplete records were excluded.

The flow diagram is illustrated in Figure 1.

2.2. Ethical approval

The study was approved by the Baskent University Institutional Review Board and Ethics Committee (Project No: E-.94603339-604.01-422464 KA25/24) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

2.3. Data collection

Demographic data, comorbidities, dialysis duration, and clinical findings were extracted from electronic medical records. Because inflammatory biomarkers may be influenced by dialysis-related inflammatory activation, laboratory parameters used to calculate inflammatory indices were obtained from routine preoperative blood tests. For patients in the AC group, blood samples were collected at the time of hospital admission prior to surgical intervention. For patients in the RT group, blood samples were obtained within 24 hours before surgery and prior to the scheduled dialysis session.

2.4. Calculation of systemic inflammatory indices

The following systemic inflammatory indices were calculated using routine complete blood count

• NLR = neutrophil count/lymphocyte count.
• SII = (platelet count × neutrophil count)/lymphocyte count.
• SIRI = (neutrophil count × monocyte count)/lymphocyte count.
• PIV = (neutrophil count × platelet count × monocyte count)/lymphocyte count.

2.5. Histopathological evaluation

Histopathological evaluation of cholecystectomy specimens had been performed as part of routine clinical practice in the Department of Pathology. All specimens had been fixed in 10% neutral buffered formalin and processed according to standard histopathological protocols.

Gross examination reports were reviewed for the presence of gallstones, gallbladder wall thickening, mucosal ulceration, purulent exudate, fibrin deposition, hemorrhage, perforation, and any tumoral or polypoid lesions.

Typically, at least 3 representative tissue sections were obtained from different regions of the gallbladder, including the fundus, body, and neck. Paraffin-embedded sections stained with hematoxylin and eosin (H&E) were retrospectively reevaluated under light microscopy by experienced pathologists to confirm the final histopathological diagnosis.

The diagnosis of AC was defined by the presence of predominant neutrophilic infiltration, with or without associated mucosal ulceration, edema, or hemorrhage. Chronic cholecystitis was characterized by lymphoplasmacytic infiltration, fibrosis, and wall thickening in the absence of prominent neutrophilic activity. Cases demonstrating neutrophilic infiltration, regardless of accompanying chronic inflammatory changes or fibrosis, were also classified as AC (acute-on-chronic cases were included in this category).

Based on histopathological findings, patients were categorized into 2 groups for subgroup (0) chronic inflammation (absence of neutrophilic infiltration), and (1) acute or active inflammation (presence of neutrophilic infiltration).

This binary classification was applied consistently for all cases and served as the reference standard for the presence of acute inflammation in the statistical analyses.

2.6. Statistical analysis

The distribution of continuous variables was assessed using the Shapiro–Wilk test. Variables with normal distribution were compared using the Student t test, while non-normally distributed variables were compared using the Mann–Whitney U test.

Due to the retrospective design of the study, some laboratory variables were not available for a limited number of patients. Statistical analyses were therefore performed using available-case analysis, and the number of observations (n) for each variable is indicated where applicable. No imputation was performed.

A P value < .05 was considered statistically significant. All analyses were performed using Python (NumPy, SciPy, pandas, scikit-learn, and matplotlib libraries).

An exploratory receiver operating characteristic (ROC) curve analysis was performed to explore the discriminative ability of inflammatory markers – CRP, WBC, NLR, SII, SIRI, and PIV – comparing patients with histopathologically confirmed acute inflammation of gallbladder to RT group, which served as the control group (9 acute vs 17 RT cases).

Another exploratory subgroup analysis was performed within the AC group, comparing patients with histopathologically confirmed acute inflammation and those with chronic inflammatory findings (9 acute vs 22 chronic cases).

The area under the curve (AUC) with 95% confidence intervals (CI) was calculated to quantify overall diagnostic accuracy. CIs were estimated using bootstrap resampling. Optimal cutoff values were determined using the Youden index (J = sensitivity + specificity − 1), selecting the threshold that maximized the combined sensitivity and specificity. Sensitivity and specificity corresponding to the optimal cutoff were reported for primary analyses.

3. Results

3.1. Patient characteristics

A total of 48 patients with ESRD were included in the study, comprising 32 men (66.7%) and 16 women (33.3%). Based on clinical evaluation, 31 patients (64.6%) underwent cholecystectomy for AC (AC group), while 17 patients (35.4%) underwent elective cholecystectomy prior to kidney transplantation (RT group).

The AC group included 18 men (58.1%) and 13 women (41.9%), while the RT group consisted of 14 men (82.4%) and 3 women (17.6%), indicating a predominance of male patients in the RT group.

3.2. Comparison according to clinical diagnosis

The comparison of demographic and laboratory parameters between the AC and RT groups is presented in Table 1. Age was the only baseline demographic characteristic that showed a significant difference between groups, with patients in the AC group being older than those in the RT group (P < .001).

Among laboratory findings, platelet counts were significantly higher in the AC group compared to the RT group (P = .037), while serum albumin levels were significantly lower in the AC group (P = .006). No statistically significant differences were observed between the groups in CRP, WBC, neutrophil, lymphocyte, or monocyte counts, hemoglobin, blood urea nitrogen, creatinine levels, duration of dialysis, or systemic inflammatory indices, including NLR, SII, SIRI, and PIV (all P > .05).

3.3. Comparison according to histopathological findings

When patients with histopathologically confirmed acute inflammation within the AC group (n = 9) were compared with the RT group (n = 17), neutrophil counts (P = .046) and PIV levels (P = .027) were significantly higher, while albumin levels were significantly lower in patients with acute inflammation (P = .013). These findings indicate increased systemic inflammatory activation in patients with histopathologically confirmed acute inflammation.

CRP, SIRI, monocyte count, and SII were higher in the acute inflammation group but not significantly; other parameters showed no differences between groups. Comparison of laboratory parameters between histopathologically confirmed acute inflammation and RT controls is summarized in Table 2.

An exploratory ROC curve analysis revealed that among the evaluated biomarkers, PIV demonstrated the highest AUC (0.771; 95% CI: 0.569–0.935), followed by CRP (0.733; 95% CI: 0.496–0.941) and SIRI (0.732; 95% CI: 0.510–0.915).

At the Youden-derived cutoff value (80.8 mg/L), CRP showed a balanced diagnostic profile with a sensitivity of 0.667 and specificity of 0.867. PIV demonstrated perfect sensitivity (1.000) but relatively low specificity (0.471), while NLR and SII also showed high sensitivity (1.000) with limited specificity (0.412).

Overall, these results suggest that composite inflammatory markers such as PIV, together with neutrophil count and albumin levels, may better reflect histopathological acute inflammation compared with conventional markers in this cohort; however, these associations should be interpreted cautiously given the limited sample size. Table 3 shows exploratory ROC analysis of inflammatory markers for distinguishing histopathologically confirmed acute inflammation from RT controls.

Within the AC group, patients with histopathologically confirmed acute inflammation (n = 9) were compared with those showing chronic inflammatory changes (n = 22). Monocyte counts and SIRI values were significantly higher in the acute inflammation group (P = .015 and P = .048, respectively). Other inflammatory markers were numerically higher in the acute inflammation group but did not reach statistical significance (all P > .05).

ROC analysis within the AC group indicated that SIRI had the highest discriminatory performance (AUC = 0.732), followed by CRP (AUC = 0.714) and PIV (AUC = 0.689). PIV demonstrated high specificity, whereas NLR and SII showed high sensitivity but low specificity. However, given the limited number of histopathologically acute cases, these findings should be interpreted as hypothesis-generating. Table 4 shows exploratory ROC analysis of inflammatory markers for distinguishing histopathologically confirmed acute inflammation within the AC group.

4. Discussion

This study evaluated the diagnostic utility of systemic inflammatory indices in ESRD patients undergoing cholecystectomy for clinically suspected AC or prophylactic surgery prior to kidney transplantation. Our findings suggest that composite inflammatory indices, particularly SIRI and PIV, may demonstrate higher discriminatory ability for identifying histopathologically confirmed acute inflammation compared with conventional inflammatory markers such as WBC and NLR.

Diagnosing AC in ESRD patients is challenging due to chronic low-grade inflammation, immune dysregulation, and altered leukocyte profiles associated with uremia and dialysis. In this context, conventional inflammatory markers may be persistently elevated, limiting their specificity for acute pathology. In our cohort, although WBC and NLR tended to be higher in patients with clinically suspected AC, their diagnostic performance was modest, consistent with previous observations in dialysis populations.^[12–16]^

Among the routinely measured laboratory parameters, platelet count and serum albumin level appeared to be the most distinguishing variables between the AC and RT groups. Platelets are increasingly recognized as active participants in inflammatory signaling and immune modulation, acting as acute-phase reactants during systemic inflammatory responses.^[17]^ Hypoalbuminemia, on the contrary, reflects a complex interplay between malnutrition, inflammation, and catabolic status, and has been widely associated with adverse clinical outcomes in patients with chronic kidney disease.^[18,19]^ In the present study, patients with histopathologically confirmed acute inflammation also had significantly lower serum albumin levels than those in the RT group, suggesting that albumin may serve as a useful indicator of systemic inflammatory burden and clinical severity. In line with this observation, albumin-based inflammatory biomarkers such as the neutrophil-to-albumin ratio and CRP-to-albumin ratio have recently been reported as independent predictors of severe acute calculous cholecystitis and perioperative complications.^[20,21]^

Histopathological analysis revealed that only 30% of patients with clinically suspected AC exhibited neutrophilic infiltration, highlighting the limitations of clinical and radiological criteria in ESRD patients. Histopathologically confirmed neutrophilic inflammation is generally associated with more severe disease in AC. In our study, patients with confirmed acute inflammation also had higher CRP, monocyte count, SIRI, and PIV values. Among these, SIRI and PIV showed the highest diagnostic accuracy in patients with confirmed acute inflammation.

Previous studies have demonstrated that higher CRP levels are associated with increased severity of AC.^[22–25]^ Notably, mean CRP levels of approximately 120 mg/L have been reported in patients with severe or gangrenous forms of the disease. In our results, the CRP cutoff value was determined to be 80.8 mg/L. However, no histopathological diagnosis consistent with gangrenous cholecystitis was found in our cases, and no signs of ulceration or necrosis were detected. CRP, a widely used acute-phase biomarker, demonstrated a relatively balanced diagnostic profile with moderate sensitivity and specificity in ROC analysis. However, its discriminatory performance was slightly lower than that of composite indices such as PIV and SIRI. This finding may be particularly relevant in ESRD patients, in whom chronic low-grade inflammation related to uremia and dialysis may reduce the specificity of conventional inflammatory markers.

Recent studies have also suggested that systemic inflammatory indices such as SIRI and SII may reflect disease severity in AC, although evidence regarding PIV remains limited.^[26–29]^ In our analysis, when histopathologically confirmed acute cases were compared with RT controls, PIV demonstrated the highest discriminatory performance among the evaluated biomarkers, followed by CRP and SIRI. This finding may reflect the composite structure of PIV, which incorporates neutrophil, monocyte, platelet, and lymphocyte counts, thereby capturing multiple components of systemic inflammatory activation.

Within the AC group, however, SIRI showed the highest discriminatory ability for distinguishing histopathologically confirmed acute inflammation from chronic inflammatory changes. SIRI integrates neutrophil, monocyte, and lymphocyte counts and may therefore more directly reflect acute inflammatory responses driven by innate immune activation. The significant elevation of monocyte counts and SIRI values in histopathologically confirmed acute cases further supports the role of monocyte–neutrophil–mediated inflammatory pathways in acute gallbladder inflammation.

Monocytes play a central role in amplifying inflammatory responses, and their incorporation into composite indices such as SIRI and PIV may explain their improved performance in detecting active inflammation.^[30,31]^ In our study, monocyte counts were significantly higher in patients with histologically confirmed acute inflammation. Previous studies have demonstrated that monocytes also contribute to renal inflammation and fibrosis in chronic kidney disease.^[32]^

Previous studies have demonstrated that the NLR may serve as a more accurate inflammatory marker than conventional parameters such as WBC and CRP in the diagnosis of AC, with higher values being associated with increased disease severity and complications.^[33,34]^ Gojayev et al reported that NLR values above 5.65 were associated with a complication rate of 92%.^[35]^ Similarly, Beliaev et al identified an NLR cutoff value of 4.1 as a diagnostic threshold for moderate-to-severe AC.^[36]^ In another study, Efgan et al demonstrated that an NLR value above 3.79 was associated with the need for ward hospitalization, whereas values exceeding 12.39 were related to intensive care unit admission and mortality.^[11]^

In contrast, our ROC analysis demonstrated that composite inflammatory indices incorporating multiple leukocyte subsets showed better discriminatory performance than conventional markers in ESRD patients. In particular, PIV exhibited the highest diagnostic accuracy when histopathologically confirmed acute cases were compared with RT controls (AUC = 0.771), followed by CRP and SIRI. Furthermore, within the AC cohort, SIRI demonstrated the highest discriminatory ability for distinguishing histopathologically acute from chronic inflammatory changes (AUC = 0.732). These findings suggest that indices reflecting the combined contribution of neutrophils, monocytes, lymphocytes, and platelets may better reflect the intensity of systemic inflammatory activation in patients with ESRD.

Interestingly, the optimal cutoff values for composite inflammatory indices differed substantially between the 2 ROC analyses. When histopathologically confirmed acute cases were compared with RT controls, relatively lower thresholds were identified for both SIRI (cutoff = 1.36) and PIV (cutoff = 244). In contrast, within the AC cohort, markedly higher cutoff values were required to distinguish histopathologically acute from chronic inflammatory changes (SIRI cutoff = 5.14 and PIV cutoff = 2116). This difference likely reflects the fact that patients in the AC cohort already exhibit elevated baseline inflammatory activity, requiring substantially higher levels of systemic inflammatory activation to differentiate true acute inflammation. These findings may suggest that composite indices such as SIRI and PIV reflect the intensity of systemic inflammatory activation rather than merely the presence of inflammation, consistent with observations reported in previous studies evaluating inflammation-based indices in acute inflammatory conditions.^[37,38]^

Taken together, these findings highlight the potential value of composite inflammatory indices, particularly PIV and SIRI, as adjunctive diagnostic markers in the evaluation of AC in ESRD patients. While PIV appeared to better discriminate histopathologically confirmed acute cases from RT controls, SIRI demonstrated greater ability to distinguish acute from chronic inflammatory changes within the AC group. Given their routine availability, low cost, and ease of calculation, these markers may serve as adjunctive tools in clinical evaluation and may be integrated into clinical decision-making algorithms for suspected AC.

Nevertheless, this study has several limitations, including its retrospective design, single-center setting, and relatively small sample size – particularly the limited number of histopathologically confirmed acute cases – that restrict the generalizability of the findings. In addition, the effects of dialysis modality, residual renal function, medication use, and timing of laboratory assessments relative to dialysis sessions were not fully evaluated. Therefore, these results should be considered exploratory and hypothesis-generating. Prospective, multicenter studies with larger cohorts are needed to validate the diagnostic utility of these inflammatory indices in ESRD populations and establish standardized cutoff values.

Author contributions

Conceptualization: Hilal Erinanc.

**Data ** Hilal Erinanc, Gulhan Kanat Unler, Oznur Kal, Aynur Yonar.

Investigation: Hilal Erinanc, Gulhan Kanat Unler.

Methodology: Hilal Erinanc, Gulhan Kanat Unler, Aynur Yonar.

Resources: Hilal Erinanc.

Supervision: Hilal Erinanc.

Validation: Oznur Kal.

**Formal ** Aynur Yonar.

**Writing – original ** Hilal Erinanc.

**Writing – review & ** Hilal Erinanc, Gulhan Kanat Unler, Oznur Kal.