Pemetrexed Nephrotoxicity

Posted on November 23, 2011 by AJKDblog in Interview, Video // 3 Comments

eAJKD Video Interview: Kidney Tubular Toxicity of Maintenance Pemetrexed Therapy

Featuring

Kenar Jhaveri, MD, eAJKD Blog Editor

and

Authors:

Ilya Glezerman, MD
Renal Service, Attending Nephrologist
Memorial Sloan Kettering Cancer Center

Surya Seshan, MD
Chief of Renal Pathology, Professor of Pathology
Weill Cornell Medical Center

Pemetrexed is an antifolate agent approved for the treatment of advanced lung cancer.A recent publication in American Journal of Kidney Diseases discusses potential nephrotoxicity of this drug. Kidney biopsy specimens showed tubulointerstitial injury with tubular simplification, shrinkage, loss of brush border, and tubular atrophy in a more advanced case. eAJKD did an exclusive video blog with the authors Dr. Ilya Glezerman( Renal service, Memorial Sloan Kettering Cancer Center, NY) and Dr.Surya Seshan( Chief of Renal Pathology, Professor of Pathology, Weill Cornell Medical Center, NY). Check out the complete article at AJKD.

Mark // November 23, 2011 at 11:06 am // Reply

Pemetrexed is an antifolate utilized for certain cancers such as advanced non-small cell lung cancer and pleural mesothelioma. Data are emerging that like other chemotherapeutic agents, it also appears to manifest nephrotoxic potential. The paper by Glezerman et al describes 3 cases of nephrotoxicity associated with long-term high dose pemetrexed therapy. The renal lesion is primarily tubulointerstitial—acute and chronic tubular injury with associated chronic interstitial fibrosis. In an interview for the eAJKD blog by Kenar Jhaveri, two of the authors, Ilya Glezerman and Surya Seshan describe their thoughts behind the data that support the nephrotoxic potential of pemetrexed. They discuss the previously published cases and clinical trial data that support nephrotoxicity. The authors also explain why they believe that pemetrexed, and not other anti-cancer agents (anit-angiogenesis drugs and anti-EGFR drugs) administered to their patients, was the cause of nephrotoxicity. They also speculate on the pathomechanism of nephrotoxicity. They suggest that uptake of the drug through apical (folate receptor-alpha) and basolateral (reduced folate carrier) transporters of the proximal tubular cells is important to tubular toxicity. They note that polyglutamylation of pemetrexed leads to nephrotoxic effects through 1) increased affinity of the drug metabolites for enzymes involved in folate metabolism, and 2) loss of transport capacity of polyglutamylated pemetrexed, thereby allowing intra-cellular accumulation of these toxic metabolites. This ultimately leads to enhanced nephrotoxicity and manifestations such as clinical acute kidney injury and proximal tubulopathy. In their report, drug discontinuation led to stabilization of kidney function, however, chronic injury was present. The role of kidney biopsy in diagnosis and prognosis was also discussed as an important aspect of evaluating cancer patients with AKI. Finally the authors discuss the importance of training and education of nephrology fellows and clinical nephrologists in the area of Onco-nephrology. I would add that publications such as this are important for the field of nephrology and needed for clinicians to gain an understanding of nephrotoxic medications, including risk factors for drug toxicity, their mechanism of injury, and their clinical and lab presentations. This is clearly important as new medications are rapidly being released into clinical practice, particularly chemotherapeutic agents. While patients are gaining longer lives, chronic kidney disease may be one of the prices paid for this success. As nephrologists, we must work with oncologists to gain a balance between these beneficial and harmful effects for patients. The authors are to be congratulated for their clinical observation.