Zoledronic Acid-Associated Fanconi Syndrome in Patients With Cancer

Abstract

Zoledronic acid (ZA) is an antiresorptive agent typically used for fracture prevention in postmenopausal osteoporosis, malignancy-associated metastatic bone lesions, and as a treatment for hypercalcemia. ZA is excreted almost entirely by the kidney; as a result, a reduction in renal clearance can lead to its accumulation and potential renal toxicity. Although uncommon, acute kidney injury (AKI) from intravenous bisphosphonates has been described, with different patterns including tubulointerstitial nephritis, acute tubular necrosis, as well as focal segmental glomerulosclerosis. Here we present 4 patients with an underlying malignancy who each developed evidence of generalized proximal tubular dysfunction, also known as Fanconi syndrome, approximately 1 week after receiving treatment with ZA. On presentation, all patients had AKI, low serum bicarbonate levels, abnormal urinary acidification, hypophosphatemia, hypokalemia, and increased urine amino acid excretion or renal glycosuria. Based on the temporal association between ZA infusion and the development of these electrolyte abnormalities, each case is highly suggestive of ZA-associated Fanconi syndrome. Due to the severity of presentation, all required discontinuation of ZA and ongoing electrolyte repletion. Nephrologists and oncologists should be aware of this complication and consider ZA as a possible trigger of new-onset Fanconi syndrome.

Keywords: Acidosis; Fanconi syndrome; aminoaciduria; bisphosphonates; case report; glycosuria; hypophosphatemia; onconephrology; proximal tubular dysfunction; proximal tubule; zoledronic acid (ZA).

Figure 1.. Time course of Zoledronic Acid Infusion and Resulting Laboratory Findings.

The first time-point shows laboratory results before ZA infusions. The second time-point for cases 1 and 2, third time-point for case 3 and fourth time-point for case 4 show the development of acute kidney injury, hypophosphatemia, metabolic acidosis and hypokalemia approximately one week after the last ZA infusion. The last time-point for all patients shows the effect of bicarbonate and electrolyte supplementation. Patient 3 had transient worsening of hypokalemia and hypophosphatemia after bicarbonate supplementation. Patient 4 had initial worsening of all parameters, until she was hospitalized at the time-point marked by the blue arrow. Black arrows indicate ZA infusions. The blue arrow indicates hospital admission time points for patients 1,3 and 4. Note that patient 3 and 4 had started the ZA infusion series 2 and 6 months, respectively, prior to the diagnose of Fanconi syndrome. Left axis indicates the ranges of creatinine (mg/dL), phosphorus (mg/dL), and potassium (mEq/L). Right axis indicates values for bicarbonate (mEq/L).