What are the potential causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in an adult or elderly patient with impaired renal function?

Causes of SIADH

SIADH results from a diverse array of etiologies including malignancies (particularly small cell lung cancer), CNS disorders, pulmonary diseases, medications, and postoperative states, with drug-induced causes being among the most common and reversible in clinical practice.

Malignancy-Related Causes

Small cell lung cancer (SCLC) is the most common malignant cause of SIADH, occurring in approximately 15% of SCLC patients through ectopic production of vasopressin by tumor cells 1, 2. Other malignancies associated with SIADH include:

• Head and neck cancers (3% incidence) 2
• Non-small cell lung cancer (0.7% incidence) 2
• Primary brain tumors, hematologic malignancies, and various other solid tumors in isolated case reports 2

The paraneoplastic syndrome typically improves with successful treatment of the underlying malignancy 1, 3.

Medication-Induced SIADH

Drugs are a leading reversible cause of SIADH and should be the first consideration in any patient presenting with unexplained hyponatremia. High-risk medication classes include 1, 4:

Psychotropic Medications

• SSRIs and SNRIs (including escitalopram) stimulate inappropriate ADH release despite low serum osmolality 1, 5
• Tricyclic antidepressants 4
• Haloperidol and other antipsychotics 1, 4

Anticonvulsants

• Carbamazepine and oxcarbazepine have moderate to high-level evidence for causing SIADH 1, 6

Chemotherapeutic Agents

• Vincristine, vinblastine, cyclophosphamide, ifosfamide, cisplatin, and melphalan 1, 4, 2

Other Medications

• NSAIDs 1
• Tramadol (added to high-risk list in 2019) 1
• Chlorpropamide 4, 6
• Enalapril, methyldopa, pentamidine, felbamate 4

Critical pitfall: The combination of thiazide diuretics with SSRIs or other SIADH-inducing medications substantially increases risk, particularly in elderly patients 1.

Pulmonary Disorders

Intrathoracic diseases are well-established causes of SIADH 2, 7:

• Pneumonia and other pulmonary infections
• Positive pressure ventilation
• Other non-malignant intrathoracic disorders

Central Nervous System Disorders

CNS pathology frequently triggers inappropriate ADH secretion 2, 7:

• Subarachnoid hemorrhage (associated with hyponatremia in a significant proportion of cases) 1
• Traumatic brain injury
• Meningitis and encephalitis
• Brain tumors
• Neurosurgical procedures

Important distinction: In neurosurgical patients, particularly those with subarachnoid hemorrhage, cerebral salt wasting (CSW) must be differentiated from SIADH, as CSW requires volume repletion rather than fluid restriction 1, 3. Central venous pressure can help distinguish these: SIADH shows CVP 6-10 cm H₂O (euvolemic) versus CSW with CVP <6 cm H₂O (hypovolemic) 1.

Postoperative SIADH

Surgical procedures, particularly those requiring cardiopulmonary bypass, can trigger SIADH 7. The mechanism involves stress-induced ADH release and iatrogenic fluid administration in the perioperative period.

Types of Osmoregulatory Dysfunction

SIADH is not a single entity but represents different patterns of abnormal AVP regulation 8:

• Type A: High, erratic AVP fluctuations unrelated to plasma sodium changes
• Type B: Constant AVP "leak" unaffected by plasma sodium
• Type C ("reset osmostat"): Progressive AVP increases correlating with rising plasma sodium toward normal range
• Type D: No demonstrable AVP abnormality (5-10% of cases), possibly due to V2 receptor mutations or abnormal aquaporin-2 regulation 8

High-Risk Patient Populations

Elderly patients face substantially elevated risk due to age-related reduction in glomerular filtration rate and increased sensitivity to hyponatremia 1. Additional risk factors include:

• Concurrent use of multiple CNS-active medications 1
• Patients on diuretic therapy 1
• Those with malnutrition, alcoholism, or advanced liver disease (requiring more cautious sodium correction) 1

Critical Diagnostic Consideration in Renal Dysfunction

SIADH diagnosis requires adequate kidney function to demonstrate characteristic urinary findings (urine osmolality >500 mosm/kg, urinary sodium >20 mEq/L) 1, 3. In patients with chronic kidney disease (CKD stages 4-5), the diagnosis of SIADH becomes problematic because:

• Impaired GFR prevents typical urinary concentration patterns from manifesting 3
• Hyponatremia in CKD typically results from impaired glomerular filtration, altered sodium handling, and volume overload rather than inappropriate ADH secretion 3
• Alternative causes such as dilutional hyponatremia from heart failure, medication effects, or advanced kidney failure with impaired free water excretion should be considered 3

If a patient carries both SIADH and CKD diagnoses, the SIADH diagnosis should be reconsidered now that renal function is impaired 3.