Cisplatin-Induced Acute Kidney Injury and Renal Salt Wasting Syndrome

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.