WHICH DRUG IS THE GREATER CONCERN FOR RENAL FAILURE IN LUNG CANCER THERAPY – CARBOPLATIN OR PEMETREXED?

A combination of Pemtrexed (PEM) (anti-folate cytostatic) and Carboplatin (second generation platinum based) has emerged as another acceptable alternative for stage III patients with non-small cell lung carcinoma. The decision to use these drugs is a balance between extending life and managing severe adverse effects.

A case of a 48-year-old male with biopsy-proven non-small cell adenocarcinoma of lung staging cT4N3M1a reformed smoker was started on injection of PEM 760 mg along with Carboplatin 600mg in June 2024 along with vitamin b12 and folic acid supplementation. After receiving the 3rd dose of PEM and Carboplatin he developed pancytopenia with grade IV thrombocytopenia in September 2024. His total leucocyte count reached 2500 / µL and platelet 25000/µL. He had no evidence of recent infection, vitamin B12-1460 pg/ml, folic acid 5.1 ng/ml and ferritin 455ng/ml, other parameters were normal. His biochemical parameters included serum creatinine 0.7mg/dl, blood urea 25mg/dl, SGOT 40IU and SGPT-45 IU. His chemotherapy drug was held by his treating physician. After 15 days of treatment stoppage, his count improved. His treating physician restarted his chemotherapy with a 25% reduction in dose, PEM (550mg) and Carboplatin at 450mg. After the 5th cycle of PEM and Carboplatin he achieved partial remission of disease but at the cost of renal injury and transaminitis. His creatinine raised from 0.7mg/dl to 1.5mg/dl (December 2024) to 2.53mg/dl (10 January 2025). With this, he was referred to the nephrology department for a creeping rise in creatinine. His ultrasound revealed a normal sized bilateral kidney. He had bland urine sediments and <500mg /24-hour proteinuria. His tropical fever workup was negative. CRP, procalcitonin, cultures were negative. On the day of biopsy, 6 February 2025, his serum creatinine was raised to 3.55mg/dl. Light microscopy examination revealed 11 glomeruli, none sclerosed. Interstitial fibrosis and tubular atrophy were 15–20%. Tubules show prominent cytoplasmic vacuolar change and evidence of severe acute injury with epithelial simplification and loss of brush borders. Scattered inspissated hyaline/ proteinaceous coarse granular cast and sloughed epithelial cells are seen in the tubular lumina. Focal chronic interstitial inflammation admixed with few eosinophils and patchy interstitial edema present. Arteries show mild medial thickening. Arterioles reveal focal hyalinosis lesion and vacuolization in smooth muscle cells. The immunofluorescent examination showed negative expression of immunoglobulins IgG, IgA, IgM, complement fragments C3, C1q and k, l light chains in glomeruli, tubules and vessels.

With this biopsy report, his chemotherapy was stopped and was initiated on prednisone 1mg/kg/day and along with mycophenolate mofetil (MMF) 500mg twice daily. After 15 days of therapy, his creatinine started to decline and after 2 months of treatment with a tapering steroid dose, his creatinine was 1.1 mg/dl (April 2025). After 3 months of therapy, MMF and prednisone were stopped.

Cancer patients are already at increased risk of developing renal insufficiency. For treatment of non-small cell lung cancer, the most common nephrotoxic anti-cancer drugs are platinum- agents and checkpoint-inhibitors. Incidence of Carboplatin induced acute kidney injury involving focal tubular necrosis and acute interstitial nephritis is very lower. On the other hand, PEM, inhibiting key enzymes within the folate metabolic pathway and impending the synthesis of purine and thymidine nucleotides. Kidney injury caused by PEM exhibits acute tubular injury, nephrogenic diabetes insipidus, and renal tubular acidosis.

Based on a literature review, I believe Carboplatin is a more likely cause of a recovering acute kidney injury (AKI) compared to PEM, which is more commonly associated with non-recovering kidney dysfunction. Several key differences in their mechanisms of nephrotoxicity support this distinction. Both drugs were withheld because it was impossible to differentiate which one was causing a kidney injury—is consistent with standard clinical practice. This precautionary approach prioritizes patient safety by removing all potential causes of a serious side effect.