Zoledronic Acid–Associated Fanconi Syndrome in Patients With Cancer

Abstract

Zoledronic acid (ZA) is an anti-resorptive agent typically used for fracture prevention in post-menopausal 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, 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 acute kidney injury (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.

Introduction

Fanconi syndrome, characterized by glycosuria, aminoaciduria and phosphate wasting, usually occurs in the setting of direct tubular toxicity from medications, paraproteins, or heavy metals¹.

Zoledronic acid (ZA) is an anti-resorptive agent for bone that is often used at high doses for metastatic bone lesions. Acute kidney injury (AKI) from intravenous bisphosphonates is uncommon, but can manifest as acute tubulointerstitial nephritis (ATIN), acute tubular necrosis, as well as focal segmental glomerulosclerosis². Fanconi syndrome has rarely been reported as a complication of ZA treatment^3–8. Here we present 4 patients with cancer who developed Fanconi syndrome after receiving ZA at 2 academic medical centers.

Case Reports.

The median age was 67 years (range 62-74) (Table 1). All 4 patients were white; 3 were females and 1 was male. All patients received intravenous ZA (dose range 3-5 mg) over 15-30 minutes for fracture prevention from skeletal metastases. The mean time from the last ZA dose to the onset of laboratory abnormalities suggestive of Fanconi syndrome was 8 ± 1.3 days.

Table 1.

Patient Characteristics and Features of Fanconi Syndrome

VARIABLE	CASE 1	CASE 2	CASE 3	CASE 4
Demographics and Comorbidities
Age	62	74	68	67
Sex	F	F	M	F
Race	White	White	White	White
Comorbidities	Breast cancer	Pancreatic cancer	Melanoma	Breast cancer
Medications
Dose of ZA (mg)	4	5	3.3	4
Rapidity of ZA Infusion (minutes)	30	15	30	15
Oncologic treatment1	Palbociclib, letrozole	Gemcitabine	Nivolumab and ipilimumab	Vinorelbine
Time to FS2 (days)	9	7	60	180
Serum Levels 3
Creatinine (mg/dl)	1.26 (+)	1.7 (+)	0.8	1.2 (+)
Sodium (mmol/L)	138	141	140	136
Chloride (mmol/L)	107	110 (+)	114 (+)	111 (+)
Potassium (mmol/L)	4	3.4 (−)	2.2 (−)	2.8 (−)
Bicarbonate (mmol/L)	18 (−)	19 (−)	16 (−)	15 (−)
Magnesium (mEq/L)	2	2.4	2	1.5
Glucose (mg/dL)	117	149	90	96
Calcium corrected for albumin (mg/dl)4	8.8	8.7	7.2 (−)	9
Phosphorus (mg/dl)	1.9 (−)	2.2 (−)	1.7 (−)	1.1 (−)
Uric Acid (mg/dl)	1.6 (−)	N/A	1.9 (−)	N/A
Urine chemistries
FePi (%)5	48 (+)	N/A	30 (+)	N/A
FeUA (%)5	45 (+)	N/A	39 (+)	N/A
Urine anion gap	61 (+)	N/A	27 (+)	41 (+)
Urine amino acids	(30/42) (+)	(26/42) (+)	(14/42) (+)	N/A
Urine pH	7	7.5	7	6.5
Urine glucose	2+ (+)	4+ (+)	neg	2+ (+)

¹Concurrent chemotherapy at the time of Fanconi syndrome. Complete list of medications prescribed within one month of Fanconi syndrome for patient 1 were: amlodipine, atorvastatin, glimepiride, letrozole, levothyroxine, losartan, palbociclib, prochlorperazine. For patient 2: gemcitabine, aspirin, clopidogrel, atorvastatin, ezetimibe, lisinopril, ondansetron, prochlorpezapine, quetiapine, tramadol. For patient 3: nivolumab, ipilimumab, dronabinol, megestrol, nortriptyline, zolpidem. For patient 4: vinorelbine, citalopram, levothyroxine, losartan, metoprolol, ondansetron, prochlorperazine, oxycodone.

²Time to Fanconi syndrome (FS) in Table 1 is defined as the number of days between the first dose of the infusion series of zoledronic acid and the detection of FS. The time from the last dose of ZA to onset of FS was 9,7,7 and 10 days in cases 1-4, respectively. Note that patient 1 had received ZA every 3 months for 2 years, followed by a 1 year pause, and then resumption of ZA (with FS developing 9 days later). Patient 2 had received ZA 1 year prior, and then resumed treatment 7 days prior to detection of FS. Case 4 had first received ZA 10 years prior and then resumed treatment 6 months before FS detection.

³Serum levels indicate laboratory values at the time of diagnosis of Fanconi syndrome. Levels of sodium, chloride, potassium, and bicarbonate represent those checked on the day of diagnosis. Other serum laboratory values were checked within 72 hours of the diagnosis. Laboratory parameters that are abnormally elevated or decreased are noted with a “(+)” or “(−)”, respectively.

⁴Calcium correction for serum albumin: Corrected calcium (mg/dl) = measured total Ca (mg/dl) + 0.8 (4.0 − serum albumin [g/dl]

⁵Fractional excretion of uric acid was calculated as [Uric Acid (Urine) * Creatinine (Serum)] / [Uric Acid (Serum) * Creatinine (Urine)] * 100 and fractional excretion of phosphorus as [PO4 (Urine) * Creatinine (Serum)] / [PO4 (Serum) * Creatinine (Urine)] * 100.

Abbreviations: F, Female; FePi, fractional excretion of phosphorous; FeUA, fractional excretion of uric acid; FS, Fanconi syndrome; M, Male; NA, Not available; ZA, zoledronic acid

Prior to ZA, all patients had an estimated glomerular filtration rate of greater than 60 mL/min/1.73 m². Renal imaging revealed no hydronephrosis or nephrocalcinosis. Patient #3 was receiving an immune checkpoint inhibitor (ICPi), but none of the patients were taking other medications associated with Fanconi syndrome. Nephrology was consulted in all cases. A diagnosis of Fanconi syndrome was made by 2 adjudicating nephrologists (IPC, SG).

Case 1

Patient #1 was diagnosed with metastatic breast cancer 5 years prior to presentation. She previously received treatment with ZA for two years, but this was held one year before presentation due to jaw osteonecrosis. Two days prior to presentation, she was prescribed ZA again due to progressive bone metastases. Within 48 hours of ZA (4 mg), she developed nausea and vomiting. Five days later, she presented to the hospital with malaise and was found to have a serum creatinine (SCr) of 1.8 mg/dL from 0.96 mg/dL. She also had new hypokalemia, with potassium decreasing from 4 mEq/L to 2.6 mEq/L. After treatment with 200 mEq/L of potassium chloride and 2 liters of 0.9% normal saline in the first 24 hours of hospital admission, her SCr improved to 1.2 mg/dL and hypokalemia gradually improved. She was also noted to have hypophosphatemia (1.9 mg/dL), a low serum uric acid at 1.6 mg/dL, and a decreased serum bicarbonate (18 mEq/L) (Figure 1 and Table 1). Her fractional excretion of phosphorous was calculated to be 48% and her fractional excretion of uric acid was 45%. She had a positive urine anion gap, elevated urine amino acids (30/42), and new glycosuria. ZA was held, and her electrolytes normalized with supplementation. At one-year follow-up, her electrolytes remained normal on potassium-phosphate tablets.

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).

Case 2

Patient #2 had a history of pancreatic adenocarcinoma for which she received gemcitabine. One year prior to presentation, she received a single 5 mg dose of ZA for without complications. After she was treated with a second 5 mg dose, in addition to her weekly gemcitabine, follow-up laboratory results 1 week later were notable for AKI with a rise in SCr from 1 mg/dL to 1.7 mg/dL. Her potassium decreased from 4.7 mEq/L to 3.4 mEq/L, and serum bicarbonate dropped from 23 mEq/L to 19 mEq/L. She had no clinical evidence of thrombotic microangiopathy (TMA). Urine chemistries revealed new glycosuria (4+) and elevated urine amino acids (26/42). ZA was discontinued, and she was treated as an outpatient with potassium-phosphate and sodium bicarbonate with normalization of electrolytes at 1 month follow-up.

Case 3

Patient # 3 was diagnosed with melanoma with brain metastases 14 months prior to presentation and received treatment with nivolumab. Six months after starting immunotherapy, he developed autoimmune hepatitis and AKI thought to be secondary to the ICPi. His renal and liver function normalized with discontinuation of the ICPi and a course of oral prednisone. Two months prior to presentation, he was prescribed monthly ZA (3 mg). Eight days after his second infusion of ZA, he developed nausea and diarrhea requiring hospital admission. Work-up revealed AKI (SCr 1.4 mg/dL from a baseline of 1 mg/dL), new hypokalemia (potassium 2.8 mEq/L from 3.7 mEq/L prior to zoledronate), new hypophosphatemia (serum phosphorus 1.7 mEq/L from 3.5 mg/dL), and metabolic acidosis (serum bicarbonate 16 mEq/L from 24 mEq/L). Treatment with prednisone at 1 mg/kg resulted in resolution of diarrhea, SCr returned to baseline, and he was discharged from the hospital. Nevertheless, his electrolyte abnormalities persisted and 10 days later he was readmitted to the hospital with weakness. Laboratory results on admission showed primarily metabolic acidosis (pH 7.31, partial pressure of carbon dioxide (PCO2) 26 and HCO3 of 12), severe hypokalemia of 2.2 mEq/L, hypocalcemia (ionized calcium 1.08 mmol/L), hypophosphatemia (phosphorus of 1.7 mg/dL), and hypouricemia (uric acid of 1.9 mg/dL). Urine chemistry showed a pH of 7 with a positive anion gap (27), elevated urine amino acids (14/42), and a urinary calcium/creatinine ratio of 0.63. A diagnosis of combined proximal and distal renal tubular acidosis (RTA) was made. Serologic workup for distal RTA was negative and he received treatment with potassium phosphate, sodium citrate, and calcium carbonate. At two-month follow-up, he remained on oral electrolyte repletion with refractory hypophosphatemia.

Case 4

Patient #4 was diagnosed with invasive breast cancer 19 years before presentation. She also had a past medical history notable for Crohn’s disease. Serum electrolytes were normal at baseline and her Crohn’s disease was in clinical remission. Ten years before presentation, she was treated with ZA at a dose of 4 mg every month for skeletal metastases, but this was discontinued after five years due to “jaw problems.” Six months prior to presentation, she resumed ZA infusions (3.5 mg monthly) due to hypercalcemia and bone metastases, including two doses of 4 mg IV ZA within 2 weeks. Ten days after the second dose, she developed mild hypophosphatemia. Three weeks after the infusion, she had worsening weakness, requiring hospitalization. On admission, her work-up was notable for AKI (SCr of 1.2 mg/dL from 0.8 mg/dL on month before), hypophosphatemia (1.1 mg/dL), hypokalemia (2.8 mEq/L from 4 mEq/L), and metabolic acidosis (venous pH 7.27, PCO2 33, HCO3 15). Urine chemistry revealed a urine pH of 6.5 (after receiving sodium bicarbonate), a urine anion gap of 41, and renal glycosuria (2+). She was treated with electrolyte repletion with improvement in her metabolic parameters; however, she was transitioned to comfort care 2 months later.

Discussion

In all four cases, patients with solid organ tumors developed proximal tubular dysfunction within 10 days of the last ZA infusion. All had abnormal urinary acidification, hypophosphatemia, hypokalemia, and increased urine amino acid excretion or renal glycosuria. There was a clear temporal association between the infusion of ZA and Fanconi syndrome.

All four cases had stage 1 AKI at presentation. Because reduced renal clearance results in ZA accumulation, AKI may have contributed to higher peak levels of ZA^9,10. Rats treated with supratherapeutic doses of ZA demonstrate dose-dependent proximal tubule degeneration and necrosis¹¹. Mechanistically, ZA can exert its toxic effect by internalization via fluid phase endocytosis, particularly at higher concentrations¹². In proximal tubular cell models, ZA can cause dysregulation of fatty acid metabolism and TGF-β signaling, leading to increased cell permeability and apoptosis¹³. In one case report of ZA-associated AKI with Fanconi syndrome, the patient had atrophy and infiltration of the proximal tubules on biopsy⁷, correlating with the findings in experimental models. However, prior case reports lacked detailed descriptions of ZA use or the management of the resulting electrolyte abnormalities^3–8,14.

In addition to ZA, patients 2 and 3 received gemcitabine and nivolumab, respectively. Gemcitabine is associated with TMA; however, our patient had no features consistent with TMA¹⁵. Patient 3 had a history of extrarenal immune-related adverse events from nivolumab including hepatitis and colitis. ICPis are more commonly associated with ATIN¹⁶, but cases of distal and proximal RTA have been described¹⁷, and it is possible that immunotherapy contributed to the patient’s clinical presentation and laboratory abnormalities^18,19.

Fanconi syndrome is a well-known complication of paraproteinemia and some cancers ²⁰. Serum electrophoresis (SPEP) was negative for monoclonal disease at presentation in patients 2 through 4. Patient 1 did not have an SPEP, but lacked any other clinical or laboratory findings suggestive of a monoclonal gammopathy.

This is the largest series of ZA-associated Fanconi Syndrome to date; however, there are limitations. Blood gases were not checked at presentation in patients 1 and 2; we are therefore unable to rule out respiratory acid-base disorders. Renal biopsies were not performed. We did not have urinary bicarbonate levels or data from bicarbonate titration tests, nor were urinary electrolytes timed to urine creatinine to confirm phosphate or potassium wasting in patients 2 and 4. Nevertheless, glycosuria and aminoaciduria were highly suggestive of proximal tubular injury.

In summary, while rare, Fanconi syndrome is a serious complication of ZA administration, especially when given at higher doses. All 4 patients required persistent electrolyte supplementation. Nephrologists and oncologists should be aware of this unusual complication and consider ZA as a possible offender in a patient with new-onset Fanconi syndrome.