Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.3 Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.4 Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.5
The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.6 This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.
Case Presentation
A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.
Investigations
We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FENa) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.
We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.
Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FEurate) was 21.9%.
Differential Diagnosis
The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FENa in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).
