Cisplatin was discovered more than 40 years ago, and is still widely used in chemotherapy regimens for many different types of cancer. Its wider use has been limited by toxicities, one of which is nephrotoxicity. Nate Hellman also wrote about cisplatin nephrotoxicity here.
I was recently consulted on an oncology patient with suspected cisplatin nephrotoxicity. The patient had hematuria with dysmorphic red blood cells on microscopy, and I wondered whether this could be a manifestation of cisplatin toxicity. The answer I found was: maybe.
Early clinical manifestations of the renal effects of cisplatin include a uniformly present polyuria. There is early polyuria at about 24-48 hours, which resolves, but is followed by a late phase between 72 and 96 hours after administration. Hypomagnesemia is a common complication and is likely due to a renal defect in magnesium reabsorption. Hypomagnesemia results in secondary hypocalcemia and hypokalemia. An incomplete distal RTA can also occur. The fall in GFR accompanying cisplatin nephrotoxicity is usually seen about 10 days after administration. A nice review of nephrotoxicity is here.
Preexisting kidney disease predisposes patients to nephrotoxicity because about 50% of cisplatin is excreted in the urine 24 hours after administration. Most of that actually appears in the first hour. Platinum is extensively protein-bound, and free platinum is freely filtered at the glomerulus and excreted unchanged in the urine. However, uptake of platinum does occur, primarily in the proximal tubule. When it enters the tubular cell it undergoes biotransformation and leads to apoptosis. The mechanism of renal damage is complex and multifactorial and due to activation of pathways that lead to production of TNF- α and subsequent inflammation. A review of these complex pathways is found here. The proximal tubular damage can result in glucosuria and amino aciduria. The glucosuria may also occur with cisplatin induced glucose intolerance. Salt wasting has also been reported with cisplatin.
Pre-hydration with saline for a goal urine output of 3 to 4L per day, drug dosage decrease (toxicity is generally dose-related), and screening for renal abnormalities are the most accepted ways to prevent nephrotoxicity. Mannitol and furosemide have been studied as preventative agents, but results have not been uniformly promising. Sodium thiosulphate is another potential protective agent, however there is some concern that it may affect the antitumor activity of cisplatin. Liposomal preparations of cisplatin are being studied and may be less nephrotoxic than the original preparations.
Proximal tubular damage, however, doesn’t explain my patient’s dysmorphic red blood cells. Cisplatin has also rarely been associated with a thrombotic microangiopathy that could possibly explain them. TMA is more commonly seen with cisplatin in combination with bleomycin and gemcitabine, but has occurred with cisplatin alone or with other drugs. He did not have schistocytes on peripheral smear and renal dysfunction was mild, so pheresis was not considered. It is possible that he had an underlying glomerulonephritis that was not previously recognized, but given his platelets of 17 and a single kidney on imaging, we didn’t plan to biopsy to find out. He did not receive any further cisplatin.
Emily Petersen, MD