a 53-year - old african man was diagnosed with unknown primary undifferentiated carcinoma with mediastinal lymph nodes and thrombosis of superior vena cava in 1993 .
the patient was initially treated by 8 cycles of chop ( cyclophosphamide , adriamycin , vincristine , and prednisone ) .
he relapsed in 1996 with spinal bone metastases treated by laminectomy , radiotherapy and pfl - vp16 ( cddp , 5fu , leucovorin , etoposide ) . in 1999 he relapsed again with mediastinal lymph nodes treated by 3 cycles of navelbine and cisplatin followed by 3 cycles of carboplatin and navelbine with > 70% treatment response .
biopsy at that time revealed large - cell carcinoma of bronchial or thymic origin . in 2002
newly discovered bone , pulmonary and mediastinal metastases were treated successively with taxotere / gemcitabine ( 6 cycles ) , navelbine / xeloda ( 6 cycles ) , iressa ( 6 months ) and tarceva ( 8 months ) . in 2005 , pemetrexed was maintained for only 4 cycles , then was suspended due to hematoxicity despite clinical efficiency .
no maintenance treatment was used until april 2007 , when new bone metastases were discovered .
the patient was hence treated with pemetrexed , as it once showed its efficacy in 2005 .
after the sixth cycle , laboratory examination revealed serum creatinine 400 mol / l , metabolic acidosis ( plasma bicarbonate 21 mmol / l ) , sodium 145 mmol / l , potassium 4,5 mmol / l , urea 21 mmol / l .
a 24-h urine collection on the 2nd hospital day revealed a 0.55 g proteinuria without hematuria or leukocyturia .
a kidney biopsy was performed showing acute tubular necrosis ( atn ) associated with chronic interstitial fibrosis ( fig .
his current renal function remained stable after 6 months follow - up of the acute renal failure ( arf ) episode with a stable serum creatinine level of 380 mol / l .
our patient experienced severe acute kidney injury related to atn and interstitial fibrosis following sequential treatment with pemetrexed for a metastatic undifferentiated carcinoma .
only few cases of arf due to pemetrexed have been reported . in a patient treated for metastatic non - small cell lung cancer , arf was associated with nephrogenic diabetes insipidus and distal renal tubular acidosis following 3 doses of pemetrexed ( 500 mg / m ) . at discharge 1 month after admission , the patient still demonstrated polyuria , hypokalemia , and metabolic acidosis despite recovery to a creatinine level of 1.7 mg / dl . in a second patient with unresectable pleural mesothelioma , pemetrexed ( 500 mg / m ) and cisplatin ( 75 mg / m ) for 3 cycles
, then pemetrexed as a single agent induced arf appearing at the sixth cycle of pemetrexed .
eighteen cases of renal failure during clinical trials of pemetrexed   have also been reported . in the phase i pemetrexed maintenance therapy ( pmt ) study evaluating toxicity as primary end point , 8% of patients with malignant pleural mesothelioma treated with high doses ( 700 mg / m ) of pemetrexed experienced reversible grade 1 or 2 renal failure : creatinine clearance decreased from 88  21 ml / min at the end of the induction therapy to 77  26 ml / min at the end of maintenance therapy ( p < 0.05 ) .
no grade 4 toxicity was observed . in phase iii trials , all grades of renal failure and grade 4 requiring dialysis
were reported in 2.4 and 0.6% of patients , respectively . in all studies , baseline creatinine clearance ( estimated using the cockcroft - gault formula )
indeed , pemetrexed - induced renal toxicity may potentiate an enhanced myelosuppressive response to pemetrexed . in an initial phase
i study   the development of severe toxicity appeared to correlate most strongly with baseline renal function .
patients with an estimated creatinine clearance value less than 80 ml / min were more likely to develop severe myelosuppression ( grade iv neutropenia ) than those with a creatinine clearance more than 80 ml / min .
this suggests that initial dosing should be based on the area under the curve as currently utilized for carboplatin rather than on body surface area and renal function .
this idea was confirmed by an analysis of 10 phase ii clinical trials . in a phase
i dose escalation trial including patients with various degrees of renal dysfunction , pemetrexed seems to be well tolerated at doses of 500 mg / m with vitamin supplementation in the case of creatinine clearance = 40 ml / min .
the fda even recommends a creatinine clearance of greater than 45 ml / min as the threshold for administering the drug .
an experimental study demonstrated that in kidney proximal tubule , the folic acid is reabsorbed via renal folate receptors and brush - border membrane vesicles .
the hypothesis is that the antifolate , like the folic acid , would be less reabsorbed by urine alkalinisation and increasing urine flow rate by hydration . on the other hand ,
thymidine is described as an antidote for pemetrexed - related toxicity in a clinical report , though in that report the concomitant use of hemodialysis complicates the interpretation of this favorable outcome . in summary ,
 we report a patient with unknown primary undifferentiated carcinoma who developed acute renal failure associated with interstitial fibrosis following pemetrexed therapy . despite drug withdrawal , renal function remained altered and the patient experienced chronic renal insufficiency . 
 pemetrexed disodium ( alimta ) is a multitargeted antifolate agent approved by the food and drug administration ( fda ) for patients diagnosed with mesothelioma and non - small cell lung cancer . 
 this drug is almost exclusively cleared by renal excretion [ 1 ] . 
 the most common side effects are hematologic dose - limiting toxicities and nonhematologic toxicities including fatigue , diarrhea , nausea , mucositis and rash . 
 although few cases of renal failure have been published , no study has reported on the renal pathological findings in this setting . 
 we present a case of acute tubular necrosis associated with interstitial fibrosis after pemetrexed therapy . 
Case Report
Discussion