Case Presentation: A 68-year-old female with non-Hodgkin’s lymphoma treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) and recent autologous stem cell transplantation, who presented with poor oral intake due to mucositis and diarrhea. Initial labs revealed sodium (Na) 146 mmol/L, potassium (K) 2.4 mmol/L, phosphorus (Pi) 2.3, and creatinine (Cr) 1.40 mg/dL comparing to baseline 1.2 mg/dL). Her electrolytes were replaced aggressively and she was rehydrated with both IV fluids and D5W. Despite above management over 3 days, her electrolyte abnormalities and renal function worsened (Na 164 mmol/L, K 1.8 mmol/L, Mg 1.5, Pi 1.4 and Cr 1.65 mg/dL). Nephrology was consulted and additional studies revealed a non-anion gap metabolic acidosis with bicarbonate of 7, urine pH at 5.0, urine osmolality at 399 mmol/L, glucosuria, and urine sodium of 52 mmol/L. She was also noted to have polyuria with 5 L urine output daily. She was diagnosed with Fanconi syndrome related to ifosfamide. In addition to continuing IV fluid and electrolyte repletion, she was started on bicarbonate supplement. Her mucositis, oral intake, and diarrhea improved with bone marrow engraftment, though she continued to require intermittent intravenous rehydration, potassium and phosphate supplementation after discharge. Her urinary retinol-binding protein (RBP) to Cr ratio was severely elevated (>199,000 mcg/g Cr).
Discussion: Fanconi syndrome is a generalized dysfunction of the proximal convoluted tubules resulting in urinary losses of bicarbonate, glucose, amino acids, phosphorus, and other solutes. Manifestations of Fanconi syndrome include mild non-anion gap metabolic acidosis, due to type 2 renal tubular acidosis (RTA), hypophosphatemia, hypokalemia, polyuria, and volume depletion(1). Fanconi syndrome can be genetic or acquired, with medications being the most common cause of an acquired disorder. Some medications associated with Fanconi syndrome include ifosfamide, cisplatin, anti-retrovirals, aminoglycoside, rifampin, and valproic acid(1, 2). Ifosfamide is an alkylating chemotherapy typically given for lymphoma, sarcomas, and bladder cancers. Fanconi syndrome is an uncommon complication with single-agent ifosfamide(2), but is dose dependent(3) and can be potentiated by concurrent platinum-based therapy, as was the case in this patient. Platinum-based therapy also contributed to the hypomagnesemia in this case. Acquired Fanconi syndrome is typically irreversible. RBP is a low-molecular weight protein that transport retinol from the liver to peripheral tissue. RBP passes freely through glomerular membranes and is reabsorbed extensively by proximal renal tubules cells; therefore, very little RBP appears in urine normally (2). The patient’s elevated RBP excretion rate was suggestive of ongoing tubular damage. Treatment for Fanconi syndrome involves treating the underlying cause and replacing the electrolytes and volume.
Conclusions: Fanconi syndrome is a generalized dysfunction of proximal renal tubules, manifesting in hypokalemia, hypophosphatemia, non-anion gap metabolic acidosis with type 2 RTA, glucosuria, aminoaciduria and dehydration. Ifosfamide and cisplatin can precipitate acquired Fanconi syndrome, which is typically irreversible. Management of acquired Fanconi syndrome consists of electrolyte and volume repletion, and treatment of underlying cause.