Urine Sodium and Urine Osmolality as Predictors for Non-Response to Treatment in Syndrome of Inappropriate Antidiuretic Hormone Secretion

Introduction

Hyponatremia, defined as a serum sodium concentration of less than 135 mEq/L, is a common electrolyte imbalance affecting 20-30% of hospitalized patients.¹ It can lead to a spectrum of symptoms, from mild to severe, including life-threatening complications.

A specific type of hyponatremia, known as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), results from an imbalance between sodium and water in the body, leading to inappropriate water retention. SIADH is characterized by the sustained secretion of antidiuretic hormone (ADH) or arginine vasopressin (AVP), even when plasma osmolality is normal or low. This condition causes hyponatremia, water retention, and dilutional serum hypoosmolality.² Understanding SIADH is crucial because of its varied causes, subtle clinical presentation, and complexities in diagnosis and treatment.

SIADH can arise from various aetiologies, including malignancies (particularly small-cell lung cancer), central nervous system disorders, pulmonary diseases, certain medications, postoperative states, and in some cases, cause is elusive.^3,4 Symptoms vary depending on the rapidity and severity of hyponatremia, ranging from mild complaints like headaches and nausea to severe manifestations such as seizures and coma.^5,6

Diagnosis of SIADH involves both biochemical and clinical evaluations, with criteria including low serum osmolality, high urine osmolality, and high urine sodium levels, while excluding other conditions like hypothyroidism and adrenal insufficiency. The primary aim of SIADH management is to correct hyponatremia and treat the underlying cause. While fluid restriction is a key therapeutic strategy, its effectiveness can vary among patients.

The variability in patient response to fluid restriction in SIADH highlights the necessity of identifying reliable predictors to adopt individualized treatment plans, avoid prolonged hyponatremia and its complications and improve patient quality of life. Current guidelines suggest using several criteria, including the degree of hyponatremia, aetiology of SIADH, and biochemical markers like urine sodium and osmolality, to predict the success of fluid restriction.^7,8 However, more research is needed to refine these predictors and enhance treatment strategies.

The study aims to explore and validate predictors of non-response to fluid restriction therapy in patients with SIADH-related hyponatremia. By identifying reliable predictors, the study seeks to optimize treatment outcomes, personalize therapeutic approaches, and set realistic expectations for patient response to fluid restriction.

Materials and methods

A prospective observational study was conducted on 171 in-patients diagnosed with SIADH in the Department of General Medicine at a tertiary care hospital in South India from May 2023 to May 2024.

The initial history, including presenting complaints and duration of symptoms, were recorded, along with routine investigations conducted as part of the hyponatremia workup.

Inclusion criteria for the study included- Euvolemia- assessed clinically, Serum sodium <125 mmol/L, Serum osmolality <275 mOsm/kg, Urinary sodium concentration >20 mmol/L, Urinary osmolality >100mOsm/kg, Normal serum cortisol [8AM: 4.82-19.5 microgm/dL] and Normal thyroid function [TSH: 0.3-4.2 microIU/mL]

Exclusion criteria for the study included- patients with hypovolemic and hypervolemic hyponatremia, hypothyroidism, Addison’s disease, pregnant females, patients on antipsychotics and diuretics.

Responders were defined as 12hour sodium increase by 3 meq/litre and 24hour serum sodium increase by 6 meq/litre. Non-responders were defined as those who failed to achieve those targets.

MS Excel was used to enter the data, and SPSS (Statistical Package for the Social Sciences) edition 21 was used for analysis. For continuous variables, the data were shown as mean and standard deviation, and for categorical variables, as percentages. The chi-square test was applied to check if symptoms could be used as predictors for nonresponse. Univariate and multivariate logistic regression analysis was performed to analyse predictors of non-response for any treatment as well as for only fluid restriction treatment. Urine Sodium and urine osmolality levels were checked as predictors by the student-t test. P value of less than 0.05 was taken as significant in statistical analysis.

Results

The study comprised 171 participants with a median age of 69 years (IQR: 58-78). Out of them, 101 were males (59.1%) and 70 were females (40.9%). The mean age for males was 64.4 years (SD = 16.4) and for females was 67.56 years (SD = 13.12). The median duration of symptoms was 2 days (IQR: 1-5).

Altered sensorium (49.1%) and generalized fatigue (29.8%) were the most common symptoms. Less frequently observed symptoms included seizures and vomiting, each occurring in 11.7% of participants ( Figure 1). The most common etiological factor in our study was pneumonia, accounting for 28.7% of cases. Malignancy (14%) and Cerebrovascular Accident (12.9%) were other common etiological factors ( Table 1).

Figure 1. Symptoms of SIADH.

In malignancies, carcinoma of the colon was associated with SIADH in 3 cases followed by prostatic carcinoma, hepatocellular carcinoma, bladder carcinoma, and pituitary tumours and other malignancies ( Figure 2).

Figure 2. Distribution in Malignancy – X axis represents absolute number of cases.

All the patients in our study received a fluid restriction of 1 Litre/day. However, most of the patients have also received hypertonic saline. 56.7% (n = 97) of patients received treatment with 1.6% hypertonic saline, and 19.3% (n = 33) of patients received 3% hypertonic saline. 24% (n = 41) of patients in the study population received only fluid restriction.

Treatment response was assessed by measuring sodium at 12 hours and 24 hours of treatment. Out of 171 patients, 53.2%(n = 91) achieved the 12-hour target and 46.2% (n = 79) achieved the 24-hour target. Among the 41 patients who received only fluid restriction, 61% (n = 25) reached the 12-hour target, while 43.9% (n = 18) met the 24-hour target.

Predictors of non-response to treatment were assessed in the entire population. Gender, the symptoms of seizures, and the 12-hour target sodium were the variables that remained significant in the multivariate model, indicating that they independently influenced the outcome after adjusting for other factors.

In the group that received only fluid restriction, a chi-square test was conducted to assess the relationship between achieving the 24-hour sodium target and various clinical symptoms. The analysis showed no significant association between reaching the target and any of the symptoms. This suggests that clinical symptoms alone may not be reliable predictors of treatment success for patients with fluid restriction. The lack of statistical significance highlights the need to explore other markers, such as biochemical parameters, to better identify patients who are more likely to benefit from fluid restriction in managing SIADH.

When examining urine osmolality, the mean value for patients who successfully achieved the target was 382 mOsm/L, compared to 491.83 mOsm/L in those who did not reach the target ( Table 3). The student’s t-test yielded a P-value of 0.044, indicating a statistically significant difference between the two groups. For urine sodium levels, the mean in the group that achieved the target was 61.2 meq/L, whereas it was 102 meq/L in the non-responding group, with a P-value of P = 0.001, showing a highly significant difference ( Table 4). These findings indicate that higher urine osmolality and urine sodium levels were associated with non-response to fluid restriction. Further multivariate analysis reinforced these results, identifying urine sodium as a negative predictor and serum sodium at 12 hours as a positive predictor for achieving the 24-hour target ( Table 2). This suggests that specific biochemical markers can be useful in predicting treatment outcomes in SIADH, aiding in the development of more individualized treatment strategies.

Discussion

This was a prospective, observational study that aimed to compare clinical, etiological, and laboratory parameters in 171 patients diagnosed with SIADH to enhance understanding and treatment strategies. By identifying specific predictors of responses to fluid restriction therapy, the research seeks to develop individualized treatment plans that improve outcomes for those affected by SIADH.

The study indicated that older individuals may have a higher likelihood of being diagnosed with SIADH with a median age of 69 years. Dyczko et al.⁹ also reported that patients with SIADH were generally older, between 53-79 years old. Our findings are also consistent with previous studies by Babaliche et al.¹⁰ which also reported most of the patients were aged between 61 and 70 years, and Sood et al.¹¹ also reported 57% of patients aged more than 60 years. This consistently observed pattern highlights the vulnerability of this age group to developing the disorder.

This study demonstrates a higher proportion of males than females in the study population, out of the 171 participants, 101 were males (59.1%) and 70 were females (40.9%). This aligns with the findings of previous studies conducted by Sood et al.¹¹ and Babaliche et al.,¹⁰ where a higher prevalence of SIADH was observed in males. Similarly, Dyczko et al.⁹ found a slightly higher prevalence in males. These variations in gender distribution may be attributed to differences in the study populations and underlying factors contributing to SIADH. Further investigation is necessary to understand the reasons behind this gender disparity.

Altered sensorium (49.1%) and generalized fatigue (29.8%) were the most common symptoms in our study, highlighting the high prevalence of neurological manifestations in SIADH as emphasized by Dyczko et al.⁹ and Sood et al.¹¹ Our study found that pneumonia was the most common cause of SIADH, accounting for 28.7% of cases. Other common causes included malignancy (14.0%), and cerebrovascular accident (12.9%). These results are consistent with a study by Shivaji et al.¹² which also identified pneumonia as the most common etiological factor for SIADH. Recognizing these underlying factors can facilitate the timely diagnosis and treatment of SIADH, leading to better patient outcomes. Winzeler et al.⁸ also found that malignancy, lung diseases, and central nervous system diseases were the common causes of SIADH.

Our study demonstrated that high urine sodium levels and high urine osmolality levels are significant predictors for non-response to fluid restriction therapy in patients with SIADH. This finding is consistent with the results of Winzeler et al.,⁸ who identified that elevated levels of both urine sodium and urine osmolality were closely associated with a lack of response to fluid restriction. Their study emphasizes the importance of these two parameters in predicting the effectiveness of fluid management strategies in SIADH. In patients with SIADH, urine sodium and urine osmolarity are typically elevated. This occurs because of the inappropriate secretion of ADH, which causes the kidneys to retain excess water. As a result, urine becomes concentrated, leading to high levels of both sodium and osmolarity in the urine. Non-responders to fluid restriction often exhibit these elevated levels, indicating that despite efforts to restrict fluid intake, their bodies fail to properly regulate water balance. This dysregulation is primarily due to the persistent effects of ADH. Even with reduced fluid intake, the kidneys continue to excrete concentrated urine. Consequently, these patients struggle to correct their hyponatremia effectively. Understanding these patterns is crucial for managing SIADH as they require additional treatment with hypertonic saline or any other line of management. It highlights the need for individualized treatment approaches to address the unique challenges faced by non-responders.

Cuesta et al.⁷ conducted a study that further supports the role of these biomarkers. They found that 60% of SIADH patients exhibited predictors of non-response to fluid restriction therapy, with 41% of the group having high urine osmolality. This suggests that urine sodium and urine osmolality play a critical role in determining whether a patient is likely to benefit from fluid restriction alone.

Furthermore, research by Decaux et al.¹³ provides additional context, revealing that 30% of patients could be successfully managed with fluid restriction alone if their initial urine osmolality was below 400 mOsm/kg H₂O. This finding implies that initial urine osmolality could serve as a critical threshold for determining the appropriateness of fluid restriction as a treatment strategy in SIADH. Our study further demonstrated that whether the 12-hour target was achieved could serve as a significant predictor of treatment response. Collectively, these studies highlight the consistent identification of initial urine sodium and urine osmolality as crucial parameters along with 12-hour serum sodium in predicting the success or failure of fluid restriction therapy in SIADH patients. Their potential utility as predictive tools can guide more effective treatment strategies.

Conclusion

In conclusion, our study highlights that SIADH is predominantly observed in the elderly, with a notable male preponderance. Neurological manifestations, particularly altered sensorium, are prevalent among patients. Common etiological factors include pneumonia, malignancy, and cerebrovascular accidents. Importantly, while specific symptoms like altered sensorium and seizures did not predict non-response to fluid restriction therapy, urine sodium levels, urine osmolarity, and early treatment response were identified as significant predictors. These findings underscore the need for careful monitoring and tailored management strategies in this vulnerable population.