Cerebral salt wasting syndrome as a probable cause of postoperative polyuria in patients with supratentorial Non-midline tumors: A prospective observational study with targeted and quantitative metabolomic approach
Neurocritical diseases such as traumatic brain injury, stroke, and subarachnoid hemorrhage are often accompanied by polyuria, a condition that causes significant fluid loss through the kidneys. This fluid loss can lead to a rapid decrease in circulating volume, thereby increasing the risk of inadequate cerebral perfusion . Additionally, polyuria is typically associated with fluctuations in serum electrolytes, including hypernatremia and hyponatremia, which can further exacerbate neurological damage . Several factors contribute to polyuria in neurocritical patients, including volume overload from excessive fluid infusion, the use of osmotic diuretics like mannitol and hypertonic sodium, central diabetes insipidus (CDI), and cerebral salt wasting syndrome (CSWS) . CDI is characterized by excessive drainage and hypernatremia, due to insufficient secretion of antidiuretic hormone (ADH) . In contrast, CSWS is marked by increased renal drainage and natriuresis, often accompanied by hyponatremia. Although the pathogenesis of CSWS is not fully understood, the release of natriuretic peptides has been proposed as a key factor involved . To date, various small molecule peptides, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), adrenomedullin (ADM) and guanylin (GN) have been reported to promote renal drainage and sodium excretion, potentially contributing to the progression of CSWS . Despite these findings, the clinical diagnosis of CSWS remains challenging due to the diversity of natriuretic peptides reported to be involved, and the lack of a comprehensive and accurate assay method. Postoperative polyuria is common in patients with intracranial tumors. However, current research primarily focuses on perioperative polyuria in patients with tumors in the supratentorial midline region (e.g., pituitary adenoma and craniopharyngiomas). This condition is typically linked to hypothalamic or pituitary damage, leading to decreased secretion of ADH and resulting in CDI . Additionally, some patients may develop polyuria after posterior cranial fossa surgery, characterized by increased urinary sodium excretion, decreased serum sodium, and elevated plasma BNP levels, indicative of CSWS . Despite these findings, there is a noticeable gap in research regarding the cause of postoperative polyuria in patients with intracranial tumors located in the supratentorial non-midline region. In this study, we aimed to address this gap by collecting clinical data from patients who underwent elective surgery for tumors in the supratentorial non-midline region to determine the incidence and the key risk factors of polyuria within 24 h after surgery in these patients. We developed a targeted, quantitative method using liquid chromatography mass spectrometry (LC-MS) to specifically detect members of natriuretic peptide family as well as ADH. As a result, we identified the causes of postoperative polyuria in patients with tumors in the supratentorial non-midline region. 

Study design In order to investigate the causes of postoperative polyuria in patients with tumors in the supratentorial non-midline region, a prospective observational study was conducted (Fig. ). This study focused on four major causes of polyuria in neurocritical illness: (1) fluid volume overload, (2) use of osmotic diuretics, (3) CDI, and (4) CSWS. Initially, perioperative clinical data were collected, including intraoperative and postoperative fluid balance, postoperative central venous pressure (CVP), inferior vena cava (IVC) width and variability, and mannitol dosage. Binary logistic regression analysis was employed to assess the impact of fluid volume and osmotic diuretics on polyuria. To further distinguish between CDI and CSWS, a liquid chromatography-mass spectrometry (LC-MS)-based targeted and quantitative assay was developed to measure six natriuretic peptides (namely ANP, BNP, CNP, DNP, ADM and GN) and ADH. Finally, changes in serum sodium and neuroendocrine hormone levels in plasma were analyzed to identify the primary cause of polyuria in patients with supratentorial non-midline tumors. Study population and sampling This prospective observational study was conducted at the First Affiliated Hospital of Sun Yat-sen University (FAH-SYSU). It included patients who underwent elective surgery for the supratentorial non-midline tumor in FAH-SYSU and were subsequently transferred to the neurosurgical intensive care unit (ICU) for the Enhanced Recovery After Surgery (ERAS) between June 2022 and December 2022. Patients were excluded based on the following criteria: (1) those with tumors located in the supratentorial midline region involving the falcine, parasagittal, sellar region (including tuberculum sellae, cavernous sinus, sphenoid ridge-clinoidal, pituitary gland), corpus callosum, septum pellucidum, hypothalamus, third ventricle, pineal ; (2) those with tumor in the infratentorial region involving the brainstem, fourth ventricle and cerebellum; (3) Those having preoperative oliguria (urine output < 400 mL per day) or polyuria (urine output > 4000 mL per day; 4) Those using medications affecting urine output, such as diuretics or desmopressin those and so on; 5) those with preoperative hypothalamic or pituitary dysfunction; 6) those with severe organ insufficiency, including cardiac, respiratory, renal, or hepatic insufficiency in the preoperative period and 7) those younger than 18 years. Definition of polyuria Postoperative polyuria was defined as either a documented total urine output (UO) of > 4000 mL per day or a mean UO of > 167 mL per hour for patients with a stay of less than 24 h . Data collection Data were collected using a standardized form. Study subjects were anonymized with code numbers (identifiers). The collected information included age, sex, height, weight, past medical history, special medication history, tumor location, tumor size, tumor histopathology, operative duration, intraoperative intake volume, intraoperative urine output, intraoperative fluid balance, postoperative CVP, postoperative IVC width and variability, postoperative intake and urine output hourly, postoperative fluid balance, postoperative drugs, postoperative blood gas analysis. Laboratory parameters were measured preoperatively, at the time of transfer to ICU (D0), and early morning on the first postoperative day (D1), including serum sodium (seNa), plasma osmolality (pOsm), serum creatinine (seCr). Myocardial enzymes including creatine kinase MB form (CK-MB), myoglobin (MYO) and troponin T (TnT) were also measured in the postoperative period. Later, the change and variability in seNa and pOsm were calculated as follows: Change in seNa=(seNa-D0)-(seNa-D1). Variability in seNa=[(seNa-D0)-(seNa-D1)] ÷ (seNa-D0). Change in pOsm=(pOsm-D0)-(pOsm-D1). Variability in pOsm=[(pOsm-D0)-(pOsm-D1)] ÷ (pOsm-D0). Development of neuroendocrine hormones detection method An efficient targeted and quantitative method was developed for measuring six natriuretic peptides (namely ANP, BNP, CNP, DNP, ADM and GN) and ADH (Fig. ). Most standards were dissolved in ddH2O, while DNP standard was dissolved in dimethylsulfoxide. Targeted metabolomics detection was performed using LC-MS. Mass spectrometric analysis was conducted on 6470 liquid chromatography triple quadrupole (LC-QqQ) system with electrospray ionization (ESI), coupled with a 1290 Infinity series HPLC (both Agilent Technologies, USA). Chromatographic separation was performed on a SunFire C18 100Å, 5 μm, 250 × 4.6 mm column (Waters, USA). Quality assessment, data evaluation, and the qualification and quantification of metabolite concentrations were performed with Masshunter software package. All metabolite concentrations in this study are reported in nanomoles per liter (nM). Sample collection and testing Blood samples were collected from patients admitted to the neurosurgical ICU for ERAS following intracranial tumors resection. Samples were collected at two time points: 0 h and 12 h after ICU admission using EDTA tubes. The blood samples were immediately centrifuged at 1600 g for 15 min at 4 °C. The plasma supernatant (≥ 500 µL) was carefully transferred to sterile frozen storage tubes using a pipette and stored at -40 °C. The collected plasma samples were sent to the laboratory on dry ice weekly and stored at -80 °C. Prior to analysis, plasma samples were pretreated with protein precipitation (PPT) to prepare them for further processing. The levels of seven neuroendocrine hormones in the plasma samples were measured using above-mentioned LC-MS method. Quantitative analysis was performed based on the standard curves established for each hormone, with the resulting detection data used for subsequent analysis. Statistical analyses The study data were analyzed using SPSS 29.0 statistical software. Quantitative variables were reported as mean and standard deviation for normally distributed data, and as median and interquartile range for non-normally distributed data. Qualitative variables were expressed using frequency and percentage. The Independent Samples t-test was used for quantitative data that followed a normal distribution meeting the chi-square test assumptions. The Mann-Whitney U test was applied to non-normally distributed quantitative data or data not meeting chi-square test assumptions. To comparing multiple sets of qualitative data, Pearson’s chi-square test was used if the total sample size was ≥ 40 and the theoretical frequencies for all classifications were ≥ 5. If the total sample size was ≥ 40 but one category had a theoretical frequency of 1 to < 5, the continuity-corrected chi-square test was used. Fisher’s exact probability method was employed if the total sample size was ≤ 40 or if any category had a theoretical frequency < 1. Risk factors of polyuria were assessed using a binary logistic regression model. Variables with p < 0.1 in the univariate analysis were selected for inclusion in the multivariate logistic regression model. The effects of polyuria on serum sodium and plasma osmolality were analyzed using a generalized linear model. Statistical significance was set at p < 0.05. Additional statistical analyses were conducted with various R packages. All chemical structures were generated with “ChemDraw” software (version 18.0), and the boxplots were generated using the “ggplot2” R package. 

In order to investigate the causes of postoperative polyuria in patients with tumors in the supratentorial non-midline region, a prospective observational study was conducted (Fig. ). This study focused on four major causes of polyuria in neurocritical illness: (1) fluid volume overload, (2) use of osmotic diuretics, (3) CDI, and (4) CSWS. Initially, perioperative clinical data were collected, including intraoperative and postoperative fluid balance, postoperative central venous pressure (CVP), inferior vena cava (IVC) width and variability, and mannitol dosage. Binary logistic regression analysis was employed to assess the impact of fluid volume and osmotic diuretics on polyuria. To further distinguish between CDI and CSWS, a liquid chromatography-mass spectrometry (LC-MS)-based targeted and quantitative assay was developed to measure six natriuretic peptides (namely ANP, BNP, CNP, DNP, ADM and GN) and ADH. Finally, changes in serum sodium and neuroendocrine hormone levels in plasma were analyzed to identify the primary cause of polyuria in patients with supratentorial non-midline tumors. 

This prospective observational study was conducted at the First Affiliated Hospital of Sun Yat-sen University (FAH-SYSU). It included patients who underwent elective surgery for the supratentorial non-midline tumor in FAH-SYSU and were subsequently transferred to the neurosurgical intensive care unit (ICU) for the Enhanced Recovery After Surgery (ERAS) between June 2022 and December 2022. Patients were excluded based on the following criteria: (1) those with tumors located in the supratentorial midline region involving the falcine, parasagittal, sellar region (including tuberculum sellae, cavernous sinus, sphenoid ridge-clinoidal, pituitary gland), corpus callosum, septum pellucidum, hypothalamus, third ventricle, pineal ; (2) those with tumor in the infratentorial region involving the brainstem, fourth ventricle and cerebellum; (3) Those having preoperative oliguria (urine output < 400 mL per day) or polyuria (urine output > 4000 mL per day; 4) Those using medications affecting urine output, such as diuretics or desmopressin those and so on; 5) those with preoperative hypothalamic or pituitary dysfunction; 6) those with severe organ insufficiency, including cardiac, respiratory, renal, or hepatic insufficiency in the preoperative period and 7) those younger than 18 years. 

Postoperative polyuria was defined as either a documented total urine output (UO) of > 4000 mL per day or a mean UO of > 167 mL per hour for patients with a stay of less than 24 h . 

Data were collected using a standardized form. Study subjects were anonymized with code numbers (identifiers). The collected information included age, sex, height, weight, past medical history, special medication history, tumor location, tumor size, tumor histopathology, operative duration, intraoperative intake volume, intraoperative urine output, intraoperative fluid balance, postoperative CVP, postoperative IVC width and variability, postoperative intake and urine output hourly, postoperative fluid balance, postoperative drugs, postoperative blood gas analysis. Laboratory parameters were measured preoperatively, at the time of transfer to ICU (D0), and early morning on the first postoperative day (D1), including serum sodium (seNa), plasma osmolality (pOsm), serum creatinine (seCr). Myocardial enzymes including creatine kinase MB form (CK-MB), myoglobin (MYO) and troponin T (TnT) were also measured in the postoperative period. Later, the change and variability in seNa and pOsm were calculated as follows: Change in seNa=(seNa-D0)-(seNa-D1). Variability in seNa=[(seNa-D0)-(seNa-D1)] ÷ (seNa-D0). Change in pOsm=(pOsm-D0)-(pOsm-D1). Variability in pOsm=[(pOsm-D0)-(pOsm-D1)] ÷ (pOsm-D0). 

An efficient targeted and quantitative method was developed for measuring six natriuretic peptides (namely ANP, BNP, CNP, DNP, ADM and GN) and ADH (Fig. ). Most standards were dissolved in ddH2O, while DNP standard was dissolved in dimethylsulfoxide. Targeted metabolomics detection was performed using LC-MS. Mass spectrometric analysis was conducted on 6470 liquid chromatography triple quadrupole (LC-QqQ) system with electrospray ionization (ESI), coupled with a 1290 Infinity series HPLC (both Agilent Technologies, USA). Chromatographic separation was performed on a SunFire C18 100Å, 5 μm, 250 × 4.6 mm column (Waters, USA). Quality assessment, data evaluation, and the qualification and quantification of metabolite concentrations were performed with Masshunter software package. All metabolite concentrations in this study are reported in nanomoles per liter (nM). 

Blood samples were collected from patients admitted to the neurosurgical ICU for ERAS following intracranial tumors resection. Samples were collected at two time points: 0 h and 12 h after ICU admission using EDTA tubes. The blood samples were immediately centrifuged at 1600 g for 15 min at 4 °C. The plasma supernatant (≥ 500 µL) was carefully transferred to sterile frozen storage tubes using a pipette and stored at -40 °C. The collected plasma samples were sent to the laboratory on dry ice weekly and stored at -80 °C. Prior to analysis, plasma samples were pretreated with protein precipitation (PPT) to prepare them for further processing. The levels of seven neuroendocrine hormones in the plasma samples were measured using above-mentioned LC-MS method. Quantitative analysis was performed based on the standard curves established for each hormone, with the resulting detection data used for subsequent analysis. 

The study data were analyzed using SPSS 29.0 statistical software. Quantitative variables were reported as mean and standard deviation for normally distributed data, and as median and interquartile range for non-normally distributed data. Qualitative variables were expressed using frequency and percentage. The Independent Samples t-test was used for quantitative data that followed a normal distribution meeting the chi-square test assumptions. The Mann-Whitney U test was applied to non-normally distributed quantitative data or data not meeting chi-square test assumptions. To comparing multiple sets of qualitative data, Pearson’s chi-square test was used if the total sample size was ≥ 40 and the theoretical frequencies for all classifications were ≥ 5. If the total sample size was ≥ 40 but one category had a theoretical frequency of 1 to < 5, the continuity-corrected chi-square test was used. Fisher’s exact probability method was employed if the total sample size was ≤ 40 or if any category had a theoretical frequency < 1. Risk factors of polyuria were assessed using a binary logistic regression model. Variables with p < 0.1 in the univariate analysis were selected for inclusion in the multivariate logistic regression model. The effects of polyuria on serum sodium and plasma osmolality were analyzed using a generalized linear model. Statistical significance was set at p < 0.05. Additional statistical analyses were conducted with various R packages. All chemical structures were generated with “ChemDraw” software (version 18.0), and the boxplots were generated using the “ggplot2” R package. 

Tumor size correlates with the incidence of postoperative polyuria in patients with supratentorial non-midline tumors A total of 30 patients (14 males and 16 females) who underwent craniotomy for tumors in the supratentorial non-midline region were included in this study based on specific inclusion and exclusion criteria (For details: See materials and methods section). Among these patients, 22 (73.3%) had normal urine output, while 8 (26.7%) experienced polyuria, defined as urine output exceeding 4000 mL/24 h (or 167 mL/h). There were no significant differences between the two groups in terms of age, gender, body mass index (BMI), tumor location, tumor histopathology, surgical duration, intraoperative fluid balance, postoperative CVP, postoperative IVC width and variability, postoperative fluid balance within 24 h and postoperative mannitol dosage (Table ). Similarly, there were no significant changes in seNa, pOsm, seCr, CK-MB, MYO and TnT at different time points between the two groups (Table ). However, tumor size was significantly larger in the polyuria group compared to the normal urine output group (Table ). Tumor size is an independent risk factor for postoperative polyuria in patients with supratentorial non-midline tumors To identify risk factors for polyuria in patients with supratentorial non-midline tumors, we conducted a binary logistic regression analysis. Univariate analysis of all potential confounders revealed that only tumor size was significant at p < 0.1 threshold (Table ). Therefore, we extended the variable screening threshold to p < 0.2, which allowed postoperative fluid balance to also meet the inclusion criteria for multivariate analysis (Table ). Both variables were then subjected to multivariate analysis using a binary logistic regression model. This analysis revealed that tumor size (OR = 1.030; 95% CI: 1.001–1.060; p = 0.041) is the only risk factor slightly associated with polyuria at 24 h post-surgery in patients with supratentorial non-midline tumors (Table ). In contrast, intraoperative and postoperative fluid balance, postoperative CVP, postoperative IVC width and variability, and postoperative mannitol dosage were not significantly associated with polyuria (Tables and ), indicating that fluid volume and osmotic diuresis are not the primary causes of postoperative polyuria in these patients. Polyuria is associated with a more pronounced decrease in postoperative serum sodium levels in patients with supratentorial non-midline tumors Next, to investigate whether polyuria impacts serum sodium and plasma osmolality in patients with supratentorial non-midline tumors, we analyzed the levels, changes, and variability of serum sodium and plasma osmolality using a generalized linear model. While there were no significant differences in serum sodium and plasma osmolality levels between the polyuria and normal urine output groups at the time of transfer (D0) and on the first postoperative day (D1) (Tables and ), the change (OR = 52.172; 95% CI: 3.382–804.730; p = 0.005) and variability (OR = 1.029; 95% CI: 1.009–1.049; p = 0.005) in serum sodium levels were significantly greater in the polyuria group (Table ) which exhibited a more pronounced decrease in serum sodium levels compared to the normal urine output group. Development of a targeted and quantitative method for detecting neuroendocrine hormones To explore the potential mechanism underlying postoperative polyuria in patients with supratentorial non-midline tumors, we developed a platform for detecting six natriuretic peptides (namely ANP, BNP, CNP, DNP, ADM and GN) and ADH using LC-MS (For details: See materials and methods section). Briefly, hormone standards were analyzed using multiple reaction monitoring mode, and calibration curves were tested for all standards (supplementary Fig. and Table ). The precursor and product ions are listed in Table . The most responsive product ion was used as quantifier, while other specific ions served as qualifiers (Fig. ). Elevated BNP is an independent risk factor for postoperative polyuria in patients with supratentorial non-midline tumors Plasma samples were collected postoperatively from 30 patients at 0 h (T0) and 12 h (T1) after transfer to ICU, and were analyzed for neuroendocrine hormones using the LC-MS based method discussed earlier. Notably, all seven neuroendocrine hormones could be detected in the patients’ plasma in a targeted manner, with good baseline separation of ion flow chromatographic peaks and reliable quantitative results (supplementary Table ). By comparing the levels of these neuroendocrine hormones in different urine output groups, we found that four hormones namely ANP, BNP, CNP, and ADH were significantly higher specifically in the polyuria group at T1 compared to T0 (Fig. ). To further investigate the effects of neuroendocrine hormones on polyuria, we performed binary logistic regression analysis to screen for independent variables. Univariate analysis showed that ANP, BNP, and ADH levels at T1 ( p < 0.1) were significantly associated with polyuria (Table ). Then, the three screened independent variables were subjected to multivariate analysis using a binary logistic regression model with the backward-conditional method. BNP at T1 (OR = 9111.901; 95%CI: 3.835-21648347.3; p = 0.022) was the only independent variable retained in the regression model. This analysis indicated elevated BNP at T1 as an independent risk factor for postoperative polyuria in patients with supratentorial non-midline tumors, suggesting CSWS as underlying cause of postoperative polyuria in these patients. 

A total of 30 patients (14 males and 16 females) who underwent craniotomy for tumors in the supratentorial non-midline region were included in this study based on specific inclusion and exclusion criteria (For details: See materials and methods section). Among these patients, 22 (73.3%) had normal urine output, while 8 (26.7%) experienced polyuria, defined as urine output exceeding 4000 mL/24 h (or 167 mL/h). There were no significant differences between the two groups in terms of age, gender, body mass index (BMI), tumor location, tumor histopathology, surgical duration, intraoperative fluid balance, postoperative CVP, postoperative IVC width and variability, postoperative fluid balance within 24 h and postoperative mannitol dosage (Table ). Similarly, there were no significant changes in seNa, pOsm, seCr, CK-MB, MYO and TnT at different time points between the two groups (Table ). However, tumor size was significantly larger in the polyuria group compared to the normal urine output group (Table ). 

To identify risk factors for polyuria in patients with supratentorial non-midline tumors, we conducted a binary logistic regression analysis. Univariate analysis of all potential confounders revealed that only tumor size was significant at p < 0.1 threshold (Table ). Therefore, we extended the variable screening threshold to p < 0.2, which allowed postoperative fluid balance to also meet the inclusion criteria for multivariate analysis (Table ). Both variables were then subjected to multivariate analysis using a binary logistic regression model. This analysis revealed that tumor size (OR = 1.030; 95% CI: 1.001–1.060; p = 0.041) is the only risk factor slightly associated with polyuria at 24 h post-surgery in patients with supratentorial non-midline tumors (Table ). In contrast, intraoperative and postoperative fluid balance, postoperative CVP, postoperative IVC width and variability, and postoperative mannitol dosage were not significantly associated with polyuria (Tables and ), indicating that fluid volume and osmotic diuresis are not the primary causes of postoperative polyuria in these patients. 

Next, to investigate whether polyuria impacts serum sodium and plasma osmolality in patients with supratentorial non-midline tumors, we analyzed the levels, changes, and variability of serum sodium and plasma osmolality using a generalized linear model. While there were no significant differences in serum sodium and plasma osmolality levels between the polyuria and normal urine output groups at the time of transfer (D0) and on the first postoperative day (D1) (Tables and ), the change (OR = 52.172; 95% CI: 3.382–804.730; p = 0.005) and variability (OR = 1.029; 95% CI: 1.009–1.049; p = 0.005) in serum sodium levels were significantly greater in the polyuria group (Table ) which exhibited a more pronounced decrease in serum sodium levels compared to the normal urine output group. 

To explore the potential mechanism underlying postoperative polyuria in patients with supratentorial non-midline tumors, we developed a platform for detecting six natriuretic peptides (namely ANP, BNP, CNP, DNP, ADM and GN) and ADH using LC-MS (For details: See materials and methods section). Briefly, hormone standards were analyzed using multiple reaction monitoring mode, and calibration curves were tested for all standards (supplementary Fig. and Table ). The precursor and product ions are listed in Table . The most responsive product ion was used as quantifier, while other specific ions served as qualifiers (Fig. ). 

Plasma samples were collected postoperatively from 30 patients at 0 h (T0) and 12 h (T1) after transfer to ICU, and were analyzed for neuroendocrine hormones using the LC-MS based method discussed earlier. Notably, all seven neuroendocrine hormones could be detected in the patients’ plasma in a targeted manner, with good baseline separation of ion flow chromatographic peaks and reliable quantitative results (supplementary Table ). By comparing the levels of these neuroendocrine hormones in different urine output groups, we found that four hormones namely ANP, BNP, CNP, and ADH were significantly higher specifically in the polyuria group at T1 compared to T0 (Fig. ). To further investigate the effects of neuroendocrine hormones on polyuria, we performed binary logistic regression analysis to screen for independent variables. Univariate analysis showed that ANP, BNP, and ADH levels at T1 ( p < 0.1) were significantly associated with polyuria (Table ). Then, the three screened independent variables were subjected to multivariate analysis using a binary logistic regression model with the backward-conditional method. BNP at T1 (OR = 9111.901; 95%CI: 3.835-21648347.3; p = 0.022) was the only independent variable retained in the regression model. This analysis indicated elevated BNP at T1 as an independent risk factor for postoperative polyuria in patients with supratentorial non-midline tumors, suggesting CSWS as underlying cause of postoperative polyuria in these patients. 

To determine the incidence and risk factors of polyuria in patients with tumors in the supratentorial non-midline region within 24 h after surgery, we conducted a prospective observational study on 30 consecutive neurosurgical cases. We found that the incidence of polyuria, defined as urine output greater than 4000 mL per day, was 26.7% (Table ). This rate is consistent with findings from previous studies on neurocritical patients . Analysis of intraoperative and postoperative data, including fluid balance, central venous pressure, and inferior vena cava width and variability, revealed no significant differences between the polyuria and normal urine output groups, indicating that fluid overload was not a contributing factor (Tables and ). Similarly, the dosage of osmotic diuretics, such as mannitol, did not correlate with the occurrence of polyuria (Table ). Our findings suggested tumor size as an independent risk factor for early postoperative polyuria (Table ). Larger tumors, which may reflect greater surgical involvement, were possibly associated with an increased risk of polyuria. However, the OR for tumor size was 1.03, which suggests that there is only a slight association between tumor size and postoperative polyuria (Table ). CDI and CSWS are the two major causes of polyuria in neurocritical patients, excluding of volume overload and osmotic diuresis . CDI results from insufficient ADH secretion and impaired water reabsorption in the distal renal tubules, leading to polyuria with elevated serum sodium . Conversely, CSWS is characterized by increased renal drainage and sodium excretion, resulting in polyuria and decreased serum sodium, which is now thought to be related to increased secretion of natriuretic peptides . We observed that while absolute serum sodium levels did not differ significantly at 0 and 12 h after ICU transfer, the polyuria group experienced a significantly greater decrease in serum sodium compared to the normal urine output group (Table ). This suggests increased sodium excretion and supports the hypothesis that postoperative polyuria in these patients is more likely to be a manifestation of CSWS. The diagnosis of CSWS requires etiologic evidence of increased natriuretic peptide secretion alongside clinical evidence of polyuria and sodium loss . A wide variety of natriuretic peptides have been discovered in the human body so far, that are secreted by cardiac myocytes, neuronal cells, and vascular endothelial cells in response to different stimuli . Current literatures suggest that the CSWS in neurological diseases may be associated with increased secretion of ANP, BNP, CNP, DNP, ADM or GN . Despite their structural differences, all these small-molecule natriuretic peptides may influence sodium and water homeostasis through the following mechanisms: (1) inhibition of vascular sympathetic tone, which relaxes the nephron’s afferent arteriole, leading to increased filtration of water and sodium through the glomerulus ; (2) suppression of angiotensin-induced sodium reabsorption in proximal tubule, resulting in a natriuretic effect ; (3) antagonism of antidiuretic hormone activity in the collecting ducts, reducing water reabsorption and producing a diuretic effect ; and (4) local production of natriuretic peptides in the adrenal medulla, which may exert a paracrine inhibitory effect on mineralocorticoid synthesis . These properties of natriuretic peptides make them promising mediators that may serve as a key link between brain injury and the development of CSWS . However, due to limitations in assay methods , previous studies often measured only one or two of these natriuretic peptides, failing to capture the full spectrum necessary for a comprehensive CSWS diagnosis . The etiologic diagnosis of CSWS remains challenging due to the diversity of these peptides and the lack of efficient detection methods. This study is the first to employ a comprehensive LC-MS assay that includes all currently known natriuretic peptide family members associated with CSWS, providing a solid foundation for diagnosing CSWS in neurological diseases. Additionally, by concurrently measuring ADH, our detection system facilitates the differentiation between CDI and CSWS based on pathophysiologic mechanisms (Fig. ). To elucidate the molecular mechanisms behind postoperative polyuria in patients with supratentorial non-midline tumors, we analyzed plasma samples using a neuroendocrine hormone detection system that measures six natriuretic peptides and ADH. We found that elevated levels of ANP, BNP, and ADH were associated with polyuria in these patients (Fig. ; Table ), suggesting that the condition is more likely linked to CSWS due to increased secretion of natriuretic peptides rather than CDI. To determine which hormone had the most significant impact on polyuria, we conducted a multivariate analysis using a binary logistic regression model, identifying elevated BNP as the key factor driving 24-hour postoperative polyuria in these patients. Previous studies have suggested several hypotheses regarding how brain injury leads to elevated serum concentrations of natriuretic peptides, particularly BNP . Firstly, natriuretic peptides are widely distributed in the central nervous system, including the cerebral cortex, hypothalamus, pituitary gland, third ventricle, brainstem, olfactory region, with specific peptides concentrated in particular areas. For instance, ANP-secreting cells are primarily found in midline regions, such as the hypothalamus and third ventricle, while BNP-secreting cells are more broadly distributed, including in the brainstem and cerebral cortex . When specific cortical and subcortical structures are injured, natriuretic peptides are released directly into the circulation . Secondly, the increased intracranial pressure that often accompanies brain injury, stimulates the production and release of natriuretic peptides from the hypothalamus. This diuretic effect helps limit further increases in intracranial pressure and their potential adverse consequences . Thirdly, the sympathetic nervous system is activated following acute brain injury, releasing large amounts of catecholamines that induce the release of natriuretic peptides from injured myocardium . Finally, hypervolemic therapy following certain conditions, such as subarachnoid hemorrhage, leads to diastolic stretching of the myocardial chambers, resulting in the release of natriuretic peptides . In our study, patients with supratentorial non-midline tumors had no underlying cardiac or renal disease preoperatively (see exclusion criteria), and markers of renal function and myocardial injury monitored postoperatively in the polyuria patients were not statistically different from those in the normal urine group (Table ). Furthermore, with the absence of postoperative hypervolemic therapy and fluid overload (Tables and ), the elevation of BNP in this study is more likely related to direct surgical injury or changes in intracranial pressure. Based on the clinical data and hormone test results, we propose that larger tumor size and more extensive surgical involvement may stimulate neurons to secrete higher levels of natriuretic peptides, primarily BNP, leading to polyuria and decreased serum sodium, which aligns with the presentation of CSWS. 

This study has several limitations. Firstly, the small sample size used in this study may affect the statistical power of the findings, resulting in high OR and wide confidence intervals . To mitigate this, we initially performed univariate analysis to perform independent variables before conducting binary logistic regression. The number of variables retained in the model was limited to three, reducing potential bias from the small sample size (Tables and ). Additionally, the small sample may not fully represent the general population, which could limit the broader applicability of the findings. Therefore, while the combination of clinical symptoms, changes in serum sodium, and natriuretic peptides measurement provides valuable and relatively reliable insights in comparison to similar studies , they should be interpreted with caution. Further studies with larger and more diverse samples are necessary to validate these findings and to deepen our understanding of the examined phenomena. Secondly, it is important to consider the inherent variability observed in the LC-MS results. Despite the use of rigorous calibration and validation protocols, fluctuations in instrument performance, sample preparation, and matrix effects can introduce variability that may impact the reproducibility and reliability of the quantitative measurements. Additionally, biological samples often exhibit heterogeneity, which can further contribute to variability in analyte concentration . These factors may lead to inconsistencies between replicates and could obscure true biological differences. Future studies should aim to standardize sample handling procedures and implement rigorous controls to mitigate these effects, thus improving the robustness of LC-MS data interpretation. Lastly, this study specifically focused on postoperative polyuria in patients with supratentorial non-midline tumors, excluding those with tumors in the supratentorial midline and infratentorial regions. Further research is required to explore the occurrence and causes of postoperative polyuria in patients with tumors in these other regions. 

This study concludes that CSWS may be the primary cause of postoperative polyuria in patients with tumors in the supratentorial non-midline region, with a characteristic decrease in serum sodium and an increase in natriuretic peptides, particularly BNP. Additionally, tumor size may exhibit a slight association with postoperative polyuria. To validate these findings, additional research involving larger sample sizes is crucial. 

Below is the link to the electronic supplementary material. Supplementary Material 1 

