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Ifosfamide (IFA) is crucial in treating various cancers. However, its use is associated with a variety of side effects, among which renal complications stand out (1). One rare but clinically significant renal manifestation is nephrogenic diabetes insipidus (NDI) (2) that poses a challenge in clinical management. Incidence of chronic renal injury secondary to IFA has been reported from 1.4 to 30%.(3-6) with IFA-related Fanconi syndrome described in 5-7% of patients treated with this drug(7). The case outlined below represents an acute side effect of IFA.
Case Report: A 59-year-old man was diagnosed with undifferentiated pleomorphic sarcoma in August 2022 (lesion in cervical region) and surgical treatment. In September 2023, new lesion in the left thoracic region was excised and tumor recurrence was found. It was high-grade mesenchymal neoplasm and the histology of differentiated liposarcoma was confirmed by immunohistochemistry. With staging T2N0M0, EC IIIA, adjuvant chemotherapy was started with IFA 3g/m² on D1, D2, D3 + Mesna 5100mg D1, D2, D3 + Doxorubicin 75mg/m² D1 followed by filgastrin 300mcg D4-D10 every 21 days. After the first cycle of chemotherapy in September 2023, he presented microscopic hematuria improved with intravenous hydration. Second chemotherapy cycle was made IFA (3g/m2), doxorubicin and mesna with standard laboratory exams and urinalysis. After two days of cycle in daily urinalysis protocol, he developed proteinuria and glycosuria in a urinary sample (with average serum glucose) and polyuria (6.000ml/24h) with low-density urine (1,010). Further, the workup showed creatinine levels (Cr) to be up to 2.7mg/dL with glomerular filtration rate (eGFR) estimated through the CKD-EPI 28.9 ml/min/1.73 m²), with baseline value Cr of 0.8 mg/dL. Tubulopathy was suspected. Hence, blood analysis showed pH 7.29, HCO3 13.9 mmol/L with a standard anion gap. Serum potassium 2.7 mmol/L, magnesium 2.5mg/dL, phosphorus 1.0mg/dL. 24-hour urine protein found was 4120 mg. After one week, renal function showed an improvement with hospital discharge using oral bicarbonate and follow-up with the nephrologist requested.
The exact mechanism behind IFA-induced renal toxicity remains not entirely elucidated, but various hypotheses have been posited. IFA undergoes hepatic activation, producing metabolites like 4-hydroxyifosfamide and acrolein. Acrolein is deemed to contribute to nephrotoxicity significantly. Such metabolites can lead to direct tubular damage, generation of reactive oxygen species, and interfere with cellular metabolism. Some risk factors for nephrotoxicity are reported, such as accumulated dose > 40-60 g/m2, reduced renal mass, young people, and application together with another nephrotoxic drug such as cisplatin. None of these conditions are present in the case presented, denoting a surprising presentation.
In this case report, we explored rare renal complications, NDI, and renal tubular acidosis associated with IFA administration. Although infrequent, these adverse effects require vigilant monitoring, particularly concerning dose, treatment duration, and patient's renal status. Early diagnosis and effective management of these complications are crucial, underscoring importance of renal monitoring as an integral component of clinical management when using this chemotherapeutic agent.