mTOR INHIBITORS AND ACUTE RENAL INJURY

Mammalian target of rapamycin (mTOR) inhibitors could be associated with acute nephrotoxicity, according to French researchers.

The team describes 4 cancer patients who developed severe acute kidney injury, apparently because of mTOR inhibition. Their report was published online June 24 in the Annals of Oncology.

"We believe that these are the first reports of unexpected acute nephrotoxicity due to mTOR inhibition," write the authors, led by Hassane Izzedine, MD, from the Nephrology Department at La Pitié-Salpêtrière Hospital in Paris. "Oncologists and nephrologists must be aware of this possible side effect, and we recommend monitoring renal function on a regular basis in cancer patients treated with mTOR inhibitors."

However, an American expert cautioned that any relation between mTOR inhibition and acute tubular necrosis, which is the adverse event in question, is unclear.

"Establishing a cause-and-effect relationship with acute tubular necrosis and this medication alone is difficult," Sheron Latcha, MD, told Medscape Medical News. She is a renal specialist at the Memorial Sloan-Kettering Cancer Center in New York City.

mTOR inhibitors are PI3K-related kinases that use mTOR complex 1 (mTORC1) and mTORC2, which have separate downstream targets and functions, to regulate cell growth, proliferation, and survival. The mTOR pathway is often aberrantly activated in cancers, and is a therapeutic target in cancer treatment. Rapamycin and analogs temsirolimus (Torisel), everolimus (Afinitor), and the investigational agent ridaforolimus (Merck and Ariad Pharmaceuticals) have shown promise in the treatment of renal cell carcinoma, and are being investigated in other types of cancer, the authors note.

However, these agents have been associated with adverse events that can be serious and/or debilitating, most notably stomatitis, rash, hyperglycemia and dyslipidemia, fatigue, and pneumonitis. In addition, mTOR agents are often associated with mild renal impairment and peripheral edema.

However, there have been no previous reports of mTOR inhibitors causing acute injury, according to Dr. Izzedine and colleagues. To the best of their knowledge, these cases studies are the first to describe this adverse event after mTOR inhibitor therapy.

"The mTOR inhibitors are primarily used by renal transplant centers," Dr. Latcha explained. "When they are used, they are not used as first-line immunosuppressive therapy. Therefore, even at renal transplant centers, the data on mTOR inhibitors are limited."

"Additionally, in the renal transplant population, many factors can cause acute tubular necrosis in the setting of mTOR inhibitor exposure," she said in an interview.

Case 1

A 57-year-old woman with a history of metastatic (pulmonary, bone) left renal cell carcinoma was treated in March 2005 with nephrectomy, zoledronic acid, interferon, and then sunitinib until disease progression in 2011. In June 2012, her serum creatinine level was 117 mmol/L, so everolimus 10 mg daily was started.

Her serum creatinine level rose to 132 mmol/L in August, 154 mmol/L in September, 284 mmol/L in October, and 777 mmol/L in November, even after her dose of everolimus was reduced.

After 6 months of treatment with everolimus, her blood pressure was 140/85 mm Hg and she weighed 45 kg (a weight loss of 5 kg). She had a serum creatinine level of 707 mmol/L, a hemoglobin level of 9.1 g/dL, a platelet count of 390.000/mm³, a haptoglobin level of 4.39 g/L, daily protein excretion of 0.4 g, and 18 red cells per high-power field.

On renal biopsy, "severe tubular necrosis was observed with denudation of tubular basement membranes, cell fragments and red cells in the tubular lumen, and cellular dismorphy," the authors report.

Hemodialysis was not required; everolimus was stopped, although zoledronic acid was continued. Four weeks later, her serum creatinine level was 200 µmol/L.

Case 2

A 59-year-old woman with a history of metastatic lung adenocarcinoma was treated in June 2009 with cisplatin and pemetrexed. Cisplatin was stopped in November 2010, and pemetrexed was continued until progression. Six months later, gemcitabine was introduced, followed by carboplatin and pemetrexed.

In early 2012, frontal metastasis was treated with stereotaxic surgery and radiotherapy, and a TORC1/TORC2 inhibitor was initiated soon afterward. The patient did not have a history of renal disease, and on treatment induction, her serum creatinine level was 96 mmol/L. It rose to 185 µmol/L at week 2 and 194 µmol/L at week 4, and treatment was stopped.

Severe tubular necrosis was seen on renal biopsy, with most of the tubes dilated, and most of the glomeruli were ischemic. Six weeks after the drug was halted, her serum creatinine level was 77 mmol/L.

Case 3

A 56-year-old woman with a history of mediastinal B lymphoma had been heavily pretreated from December 2011 to March 2012 with 8 cycles of R-CHOP (rituximab, cyclophosphamide doxorubicin hydrochloride, vincristine sulfate prednisone) and multiple ineffective chemotherapy lines, including gemcitabine and dexamethasone. She was treated with a TORC1/TORC2 inhibitor in June 2012. Her serum creatinine, which was 50 µmol/L prior to treatment, jumped to 115 µmol/L a week later. Urinalysis revealed a daily protein excretion of 0.5 g, without white or red cells. Early mild tubular necrosis was observed on biopsy.

The TORC1/TORC2 inhibitor was stopped; 10 days later, her serum creatinine level was 70 µmol/L; 6 months later, it was 60 mmol/L.

Case 4

A 73-year-old man had a history of hypertensive chronic kidney disease and a basal serum creatinine level of 200 µmol/L. He was diagnosed with mantle cell lymphoma in February 2009 and treated with 6 cycles of rituximab, doxorubicin, bortezomib, and dexamethasone, which was replaced with rituximab, dexamethasone, oxaliplatin, and citarabin in August 2010.

Maintenance therapy with temsirolimus was initiated in January 2011, and his serum creatinine level climbed from 245 to 406 µmol/L a month later. After 5 weeks of temsirolimus therapy, his blood pressure was 180/90 mm Hg, serum creatinine level was 484 mmol/L, blood urea was 34 mmol/L, hemoglobin level was 8.6 g/dL, and platelet count was 27.000/mm³.

Renal biopsy showed severe tubular necrosis, with denudation of tubular basement membranes, cell fragments, and red cells. The patient remains on dialysis.

Adverse Effects of mTOR Inhibitors

The authors emphasize that 3 patients lacked any history of diabetes mellitus, hypertension, or drug therapy with potential nephrotoxic agents. In addition, renal-related causes were excluded in all 4 cases.

A recent meta-analysis, published online May 8 in the Annals of Oncology, evaluated the incidence and risk for treatment-related mortality with mTOR inhibitors. "During our search for studies pertaining to adverse events associated with mTOR inhibitors, we found several studies that we used in our meta-analysis that identified acute renal failure as a cause of fatalities," said Marina Kaymakcalan, PharmD, from the Dana-Farber Cancer Institute in Boston, who was one of the authors of that study. "None of these studies indicated that the acute renal failure was actually acute tubular necrosis."

"I believe it is difficult to fully attribute acute tubular necrosis to mTOR inhibitor use in cases where patients have previously or are concomitantly using other nephrotoxic medication, particularly in case 1, where the patient was also on a bisphosphonate," she told Medscape Medical News. "Bisphosphonate-induced acute tubular necrosis is well known."

The authors have disclosed no relevant financial relationships.

Ann Oncol. Published online June 24, 2013. Abstract