A Case of Acquired Fanconi Syndrome Induced by Zoledronic Acid

CASE REPORT A Case of Acquired Fanconi Syndrome Induced by Zoledronic Acid Tetsuhiro Yoshinami, Toshinari Yagi, Daisuke Sakai, Naotoshi Sugimoto and Fumio Imamura Abstract A 61-year-old woman with metastatic breast cancer was diagnosed as having acquired Fanconi syndrome. In this case, the cause of this syndrome was most likely zoledronic acid (Zometa ), which had been infused intravenously at a dose of 4 mg over 15 minutes weekly because of malignancy-associated hypercalcemia. Zoledronic acid is nephrotoxic and may induce severe tubular dysfunction, which can cause development of Fanconi syndrome. Therefore, close monitoring of proximal tubular function is recommended during therapy with zoledronic acid, especially when frequent administration of zoledronic acid is needed. Key words: Fanconi syndrome, zoledronic acid, metastatic breast cancer, nephrotoxicity () () Introduction Fanconi syndrome is a generalized dysfunction of the renal proximal tubules, which causes renal losses of glucose, protein, bicarbonates, calcium, uric acid, amino acids, and other organic compounds (1). As a result, various abnormalities are found on examination of blood and urine. Zoledronic acid (Zometa ) is one of the nitrogen-containing bisphosphonates. It is effective in the treatment of hypercalcemia and bone metastasis, and widely used for various malignancies (2). However, it has been reported to be nephrotoxic (3-5), and several cases of acute tubular necrosis due to zoledronic acid have been reported (3). We encountered a breast cancer patient who developed Fanconi syndrome due to zoledronic acid. To our knowledge, this is the first case report describing Fanconi syndrome due to zoledronic acid. Case Report A 61-year-old woman with metastatic breast cancer was admitted to our hospital because of hypokalemia at the end of December 2009. She was anorexic but findings on physical examination were normal. She had been diagnosed as having breast cancer (T3N1M0 Stage IIIA, Estrogen receptor-, Progesteron receptor-,her2 3+) in January 2009, and received 4 courses of FEC (5-FU 500 mg/m 2 on day 1, epirubicin 100 mg/m 2 on day 1 and cyclophosphamide 500 mg/m 2 on day 1, repeated every 21 days) followed by 4 courses of docetaxel (75 mg/m 2, repeated every 21 days) as neo-adjuvant chemotherapy. Then breast-conserving surgery and axillary lymph node dissection was performed in mid-august 2009. On postoperative pathological examination, the efficacy of neoadjuvant chemotherapy was judged as grade 2 (6). At the end of September 2009, she was hospitalized because of malignancy-associated hypercalcemia (MAHC) due to metastatic breast cancer. Serum calcium concentration was 17.2 mg/dl (normal range, 8.1-10.4 mg/dl), and serum albumin concentration was 2.9 mg/dl (normal range, 3.9-4.9 g/dl). Metastasis to the liver from breast cancer was detected by computed tomography (CT) on admission. For MAHC, she received repeated intravenous injections of zoledoronic acid (Zometa ) at a dose of 4 mg infused over 15 minutes administered weekly from the end of Sept till the end of November. 2009. Combination chemotherapy of paclitaxel (30 mg/m 2, repeated weekly) and trastuzumab (2 mg/kg, repeated weekly after the first loading dose of 4 mg/kg) was started at the end of October 2009. MAHC was improved by zoledronic acid and the chemotherapy. In early December 2009, she was discharged but returned once a week to continue the chemotherapy. Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan Received for publication November 15, 2010; Accepted for publication January 17, 2011 Correspondence to Dr. Tetsuhiro Yoshinami, yosinami-te@mc.pref.osaka.jp 1075

Table 1. Laboratory Examination on Admission Blood examination on re-admission in December 2009 demonstrated hypokalemia, hypophosphatemia and hypouricemia (Table 1). Chemical screening of urine showed glucosuria (2+) and proteinuria (3+: 24-h urinary protein was 0.9 g). Despite glucosuria, routine blood glucose was 117 mg/dl and HbA1c was 4.7%, indicating that the cause of glucosuria was renal diabetes. Urinary examinations demonstrated that 24-h urinary potassium excretion was increased to 26.5 meq/day, and urinary anion gap was 27.2 meq/l. Fractional excretion of uric acid was 56% (normal range, 6% to 20%) and TmPO4/GFR was 0.75 (normal range, 2.3 to 4.3). Urinary β2-microglobulin (β2mg) value was 69,264 μg/day (normal range, 0-169 μg/day), which was equivalent to 197,897 μg/g Cr. Blood gas analysis showed a pattern of hyperchloremic metabolic acidosis. Bicarbonate concentration was decreased to 16.4 mmol/l, but respiratory compensation normalized the ph. Ten days after admission, adjusted serum calcium concentration was 7.5 mg/dl (serum calcium and albumin concentration were 6.1 mg/dl and 2.6 g/dl respectively), indicating hypocalcemia. Since Fanconi syndrome was suspected based on the above findings, urinary amino acid analysis was conducted. Urinary concentrations of 23 of 41 amino acids were increased (Table 2). The diagnosis of Fanconi syndrome was established by hyperaminoaciduria, renal diabetes, phosphaturia and hypophosphatemia, hyperchloremic metabolic acidosis, proteinuria, and other characteristic electrolyte abnormalities of blood and urine. Oral intake of spironolactone successfully increased the serum potassium concentration to a normal level. Intravenous or oral administration of sodium bicarbonate improved metabolic acidosis (Fig. 1), and anorexia disappeared. She was discharged at the end of January 2010. In this case, the cause of Fanconi syndrome was most likely drug related. Possible causative drugs were zoledronic acid, paclitaxel and trastuzumab. This patient stopped receiving injections of zoledronic acid after the end of November 2009. However, her breast cancer was so advanced that continued administration of combined chemotherapy with paclitaxel and trastuzumab was necessary. She continued the ambulatory chemotherapy with paclitaxel and trastuzumab, supported by oral spironolactone and sodium bicarbonate. Urinary protein and glucose became undetectable, and urinary β2-microglobulin gradually decreased to 1,415 μg/g Cr on May 2010, indicating the improvement of Fanconi syndrome. Discussion Fanconi syndrome was first described by Lignac in 1924 (1). It is characterized by multiple transport defects in the renal proximal tubules. The dysfunction leads to renal losses of glucose, protein, amino acids, bicarbonates, uric acid, and some electrolytes such as sodium, potassium, calcium, and phosphate. Cardinal features of the syndrome are hyperaminoaciduria, glucosuria despite a normal serum glucose level, phosphate wasting (phosphaturia and hypophosphatemia), acidosis, and proteinuria. Other manifestations are hypouricemia, hypokalemia, hyponatremia, hypercalciuria, and polyuria. In the present case, proteinuria, renal diabetes, hyperchloremic metabolic acidosis, hypophosphatemia and some other electrolyte abnormalities were found, which strongly suggested Fanconi syndrome. Diagnosis of Fanconi syndrome was confirmed by the demonstration of hyperaminoaciduria. Causes of Fanconi syndrome range from inherited diseases to acquired factors. Inherited diseases such as cystinosis, galactosemia and Wilson s disease are known to be associated with this syndrome. Certain drugs including cisplatin, ifosphamide, gentamicin sulfate and valproate sodium are reported to contribute to the development of the syn- 1076

Table 2. Urinary Amino Acid Analysis drome. Other causative factors include heavy metals, such as lead and cadmium and systemic disorders, such as amyloidosis, multiple myeloma and systemic lupus erythematosus. In the present case, Fanconi syndrome was thought to have been induced by zoledronic acid. The abnormalities on blood and urine examinations associated with the syndrome had not been detected before the administration of zoledronic acid, and she did not have any history of illness other than breast cancer. Based on the Naranjo Adverse Drug Reaction probability scale, a drug reaction is the probable cause of the syndrome in the present case (7). The last administration of zoledronic acid was at the end of November 2009, and Fanconi syndrome gradually improved following the discontinuation of zoledronic acid despite the continuation of other drugs. We concluded that zoledronic acid was the cause of Fanconi syndrome in this case. We cannot rule out a possibility that paclitaxel or trastuzumab may have increased nephrotoxicity of zoledronic acid. A retrospective analysis showed an increased nephrotoxicity in patients with gynecological cancers treated with paclitaxel and cisplatin as compared to those receiving cisplatin alone (8). However, we cannot find any other report suggesting an association between paclitaxel or trastuzumab and nephrotoxicity, and based on the Drug Interaction Probability Scale, the role of paclitaxel or trastuzumab in this event is doubtful (9). Zoledronic acid (Zometa ) is one of the nitrogencontaining bisphosphonates. It inhibits bone resorption, resulting in not only the improvement of MAHC but also a reduction of the risk of skeletal-related events in solid cancer patients (10-13). Significant side effects of bisphosphonates are relatively rare, but these agents are nephrotoxic (3, 4, 14). In general, patterns of nephrotoxicity include toxic acute tubular necrosis (ATN) and collapsing focal segmental glomerulosclerosis (FSGS) (4). The nephrotoxicity of zoledronic acid appears to be associated mainly with injury to the tubules (4). Markowitz et al reported 6 cases of ATN, five with multiple myeloma and one with 1077

Figure 1. The left axis shows UA (mg/dl), K (meq/l) and IP (meq/l). The right axis shows HCO 3 (mmol/l). Hypokalemia, hypophosphatemia and metabolic acidosis were improved by therapies such as oral intake of spironolactone and administration of sodium bicarbonate after admission. Paget s disease, treated with zoledronic acid (3). All six patients received intravenous monthly administration of 4 mg zoledronic acid, infused over 15 minutes. They developed renal failure with a rise in serum creatinine. Renal biopsy demonstrated toxic ATN without evidence of collapsing FSGS. The frequency and severity of nephrotoxicity of zoledronic acid depends on the length of infusion time and dosage (5). In the early clinical trials with zoledronic acid, two protocol adjustments were required to reduce its renal toxicity (11-13). One was to increase the infusion time period from 5 to 15 minutes, and the other was to reduce the dose from 8 to 4 mg every 3 to 4 weeks. Currently, it is recommended that zoledronic acid be intravenously infused at a dose of 4 mg over 15 minutes. The interval between each administration is at least a week for treatment of MAHC and 3 or 4 weeks for the treatment of skeletal metastases in patients with multiple myeloma and solid tumors. The present patient received weekly administrations of 4 mg zoledronic acid via a 15-minute infusion because MAHC was so severe that she needed to receive treatment as frequently as possible. Zoledronic acid administration was performed nine times over approximately two months. Such frequent administrations might have increased the risk of renal injury. Buysschaert et al reported a case of Fanconi syndrome induced by intravenous pamidronate (15), which is also one of the bisphosphonates and has been shown to be more nephrotoxic than zoledronic acid in rat models (16). However, there has not been any case of zoledronic acid induced-fanconi syndrome reported to date. In conclusion, zoledronic acid can induce severe tubular dysfunction, which may progress to Fanconi syndrome. Therefore, close monitoring of proximal tubular function is recommended during therapy with zoledronic acid as well as pamidronate, especially when frequent administration is needed. The authors state that they have no Conflict of Interest(COI). References 1. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Druginduced Fanconi s syndrome. Am J Kidney Dis 41: 292-309, 2003. 2. Kawada K, Minami H, Okabe K, et al. A multicenter and open label clinical trial of zoledronic acid 4 mg in patients with hypercalcemia of malignancy. Jpn J Clin Oncol 35: 28-33, 2005. 3. Markowitz GS, Fine PL, Stack JI, et al. Toxic acute tubular necrosis following treatment with zoledronate. Kidney Int 64: 281-289, 2003. 4. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int 74: 1385-1393, 2008. 5. Pfister T, Atzpodien E, Bohrmann B, Bauss F. Acute renal effects of intravenous bisphosphonates in the rat. Basic Clin Pharmacol Toxicol 97: 374-381, 2005. 6. The Japanese Breast Cancer Society. General rules for clinical and pathological recording of breast cancer (the 16th edition). (in Japanese). 1078

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