Acquired Fanconi Syndrome from Ifosfamide

Fanconi syndrome is characterized by type 2 proximal renal tubular dysfunction with subsequent electrolyte disturbances [2,3]. Proximal tubule is the first part of the nephron that actively reabsorbs approximately 65% of water, various electrolytes, glucose, amino acids, and peptides [4]. Most of the drug transporters are also located in the proximal tubules [5]; therefore, it plays a vital role in secretion and reabsorption of drugs and their metabolites. This particular syndrome has been previously associated with chemotherapy drugs, anti-viral medications, and aminoglycoside antibiotics [2]. Ifosfamide, an alkylating agent used for solid tumors [1], is known in the literature to be associated with Fanconi syndrome. Its nephrotoxic effect has been established in approximately 30% of the adult patients [5]; however, more frequently seen in children than in adults [6]. Ifosfamide also seems to have a dose-dependent risk factor in causing Fanconi syndrome [3,6].

A 47-year-old female with stage IVB squamous cell carcinoma of the cervix, colostomy placement, and hypertension was admitted for a fifth cycle of ifosfamide and mesna. She completed a five-day course of 12.3 g/m² of ifosfamide during each chemotherapy cycle, totaling to approximately 62 g/m². On admission, her basic metabolic panel was unremarkable (Table 1). As a result of the chemotherapy, she developed nausea and vomiting, and anti-emetics were not helping much. Throughout the hospitalization, the electrolytes began to decrease despite repletion. The colostomy output was negligible; however, urine output started to increase to maximum of 6.4 L. The initial thought was that she was developing electrolyte abnormalities as a result of chemotherapy-induced gastrointestinal loss. However, given that she was vomiting and not having diarrhea, the development of a metabolic acidosis did not fit the clinical picture. Therefore, we ordered a urine analysis for further investigation, and it showed a pH 6, glucose 50 mg/dL, ketone 80 mg/dL, and protein 30 mg/dL. Further evaluation with 24-hour urine collection showed urine phosphorous 1.2 g/total volume, potassium 69.2 g/total volume, and uric acid 345 mg/total volume.

*patient received 5 days of chemotherapy 

Table 1: Metabolic panel. 

She was given maintenance dose of D5LR at 100 mL/hr and her electrolytes were repleted through a peripheral IV line with potassium phosphate. She was eventually discharged on an oral regimen of potassium chloride 40 mg twice a day; phosphate-sodium-potassium 2 tablets three times a day, and magnesium 256 mg daily. Two weeks after discharge, her labs showed a normal basic metabolic panel (Table 1) and a urinalysis that was negative for protein, glucose, and ketones. 

Initially, the patient’s electrolyte imbalance was thought to have been from anorexia and non-retractable vomiting. However, in the setting of electrolyte imbalance with glucose and protein in the urine despite not having diabetes mellitus or hyperglycemia, she was diagnosed with type 2 renal tubular acidosis attributable to Fanconi syndrome due to ifosfamide.

There has been a dynamic expansion of cancer therapies. Unfortunately, many of the drugs also come with toxic side effects. Particularly with ifosfamide, there is an association with Fanconi syndrome, especially in patients with risk factors of high dose ifosfamide administration (40-60 g/m²) [3,6], young age [7], reduced kidney mass [8], and concurrent nephrotoxic medication use. Other anti-cancer medications that have been associated with Fanconi syndrome include cysplatin, nitrosurea derivates, azacytidine, mercaptopurine, vemurafenib, imatinib, idelalisib, and lenalidomide. Those with Fanconi syndrome commonly present with hypokalemia, hypophosphatemia, metabolic acidosis with serum bicarbonate >/= 15, proteinuria, and glucosuria [2]. Despite proximal tubule’s main function of water and sodium reabsorption, hypovolemia and hyponatremia are not as common due to compensatory mechanism in the distal tubules [2]. In chronic cases, some may present with bone demineralization and osteomalacia from urinary phosphate loss [2]. Severe Fanconi syndrome may also occur without an increased creatinine [2]. Treatment is usually supportive with electrolyte repletion and decrease or removal of offending agent. 

Most of the time, renal function can recover with the removal medications or toxin. In some pediatric cases, damage persisted for at least 10 years after discontinuation of ifosfamide [9,10]. Prevention of renal dysfunction can be done through monitoring renal function and electrolytes, adequate volume and electrolyte repletion, and avoidance of other nephrotoxic medications. 

Main mechanism of ifosfamide-induced Fanconi syndrome is hypothesized to be due to the interaction between the drug and human organic cation transporter 2 (hOCT2) [9]. hOCT2 causes an increased intracellular concentration in cells expressing these transporters and eventually leading to nephrotoxicity [9]. Another study showed that co-administration of cimetidine, a competitive substrate of hOCT2 prevented ifosfamide toxicity [9]. Understanding the mechanism behind nephrotoxicity and other side effects is vital in minimizing complications while receiving chemotherapy regimen. 

There have been a few case reports regarding ifosfamide-induced Fanconi syndrome, frequently seen up to 50% in children[7] but not common in adults [6]. One case report describes a 25-year-old woman who presented with prominent proteinuria (spot >300 mg/dL and 2 g/day), glucosuria, and hypophosphatemia after receiving four cycles of ifosfamide (total dose of 39 g/m²) [6]. Her blood and urine labs resolved following electrolyte repletion and close monitoring [6]. Another case describes a 61- year-old man who presented with Fanconi syndrome and diabetes insipidus after receiving one cycle of ifosfamide (total dose of 7.5 g/m²) [3]. Unfortunately, he died from uncorrected metabolic acidosis after nine days of receiving the agent [3]. A third case report also describes a 54-year-old man who presented with Fanconi syndrome and diabetes insipidus after receiving a fourth cycle of ifosfamide (total dose 44 g/m²) [11]. His symptoms and lab abnormalities completely resolved after 5 days with supportive treatment. Our patient had polyuria, but we did not perform diagnostic testing for evaluation of diabetes insipidus. In another case report, ifosfamide has shown to cause a delayed side effect of proximal tubular dysfunction; for example, a 20-year-old man developed Fanconi syndrome three months after completing his chemotherapy for his treatment of osteosarcoma [12]. 

Based on our case and others, early recognition, supportive care with electrolyte repletion, and removal of ifosfamide has shown to restore proximal tubule function. In summary, cancer patients commonly have electrolyte abnormalities as a result of chemotherapy-induced gastrointestinal side effects. However, physicians should also be aware of chemotherapy agents, especially ifosfamide, causing potential renal loss of electrolytes and metabolic acidosis.