Abstract
Keywords
Introduction
Oxaliplatin is a platinum-based antineoplastic agent that is used effectively in the treatment of colorectal cancer, typically in combination with fluorouracil. 1 The most common side effect of this drug is neurotoxicity, which manifests as acute neurosensory complex symptoms as well as a cumulative sensory neuropathy, both of which are induced or precipitated by exposure to cold. 2 Nausea and mild hematological toxicity are other side effects observed with oxaliplatin. 2 Unlike other platinum derivatives, oxaliplatin has acceptable nephrotoxicity 1 ; however, recent case reports suggest various forms of renal toxicity related to oxaliplatin in combination with other agents.3-17
To our knowledge, this is the first case report of renal tubular vacuolization with symptoms mimicking thrombotic microangiopathy in a patient on long-term chemotherapy with oxaliplatin.
Case Report
A 40-year-old woman with colon adenocarcinoma underwent rectosigmoidectomy in 2005. This was followed by adjuvant radiotherapy (45 Gy) and chemotherapy with 5-FU/LV (5-FluoroUracil/LeucoVorin) for a total of 6 cycles in another facility. She was referred to our medical center in March 2010 for further management. A computed tomography scan showed multiple abdominal and pelvic masses, and biopsy revealed metastatic disease in the abdomen and pelvis, which was deemed unresectable. Chemotherapy with mFOLFOX7 (modified/FOLinic acid/Fluorouracil/OXaliplatin) was begun for a total of 12 cycles, which resulted in partial remission of pelvic spread with no significant changes in abdominal metastatic masses. Subsequently, the abdominal wall masses were resected, and adjuvant chemotherapy with FOLFIRI (FOLinic acid/Fluorouracil/IRInotecan) for a total of 12 cycles was instituted. Although complete response in the pelvic metastases was observed, a follow-up colonoscopy and biopsy specimen of the colon-anal anastomosis site showed local recurrence of adenocarcinoma. Despite reintroduction of mFOLFOX7 for 6 cycles, abdominopelvic MRI indicated no significant changes in the rectal tumor size. mFOLFOX7 was continued for another 6 cycles; however, repeat imaging of the pelvis showed tumor progression. Another course of radiotherapy (30 Gy) and concurrent chemotherapy with XELOX (capecitabine [XELoda®]/OXaliplatin ; 8 cycles) was administered. Then, 4 months later, an abdominoperineal resection was performed and followed by adjuvant chemotherapy with 12 cycles of FOLFIRI. Follow-up abdominopelvic computed tomography revealed local recurrence, and chemotherapy with mFOLFOX7 was planned for another 6 cycles.
On June 14, 2013, during the fourth cycle of mFOLFOX7—that is, 36th oxaliplatin infusion—the patient experienced sudden abdominal pain and a transient low-grade fever. A few hours later, she developed jaundice and gross hematuria followed by oliguria; she was afebrile with a heart rate of 79 beats/min, blood pressure 120/80 mm Hg, respiratory rate 16 breaths/min, and a normal oxygen saturation. Laboratory data (Table 1) revealed a high level of creatinine, hyperbilirubinemia, elevated lactate dehydrogenase, severe anemia, and thrombocytopenia. Blood gas analysis was within normal limits.
Laboratory Tests.
Abbreviations: WBC, white blood cell; INR, international normalized ratio; LDH, lactate dehydrogenase; ND, not done.
Peripheral blood smear showed schistocytosis of <1%; direct Coombs test (direct antiglobulin test) was negative; and serological tests for HIV, HBV, and HCV were negative. Circulating immune complexes, antinuclear antibodies, cytoplasmic and perinuclear antineutrophil cytoplasmic antibodies, anticardiolipin antibody, and rheumatoid factor were negative. Blood and urine cultures were sterile. Renal ultrasound reported kidneys of normal size and texture, with no evidence of any obstruction or nephrolithiasis, and renal/abdominal color Doppler indicated normal venous and arterial blood flow.
A renal biopsy indicated acute interstitial nephritis with tubular epithelial cytoplasmic vacuolization and nuclear enlargement compatible with drug-related renal injury. Immunofluorescence staining showed no specific deposits (Figures 1 and 2).
High-power view of mixed interstitial inflammatory cell infiltration, including numerous eosinophils as well as epithelial cytoplasmic vacuolization and reactive changes (hematoxylin & eosin, ×200).
High-power view of cytoplasmic vacuolization of tubular epithelial cells and red blood cell casts in tubular lumens without inflammation (hematoxylin & eosin, ×200).
After the onset of symptoms, chemotherapy was discontinued, and the patient underwent hemodialysis for progressive acute kidney injury (AKI). Her AKI improved rapidly after 3 sessions of hemodialysis, with hematological and biochemical tests gradually normalizing during her hospitalization.
Discussion
We report the first case of oxaliplatin-induced renal tubular vacuolization. Based on the Naranjo Probability Scale, the likelihood of oxaliplatin causing the renal injury in this case is probable. 18 This occurred after 36 cycles of oxaliplatin-based chemotherapy and was associated with severe anemia, thrombocytopenia, and hyperbilirubinemia. These clinical symptoms resembled immune-mediated hemolytic anemia (IMHA) and thrombotic microangiopathy; however, a negative direct antiglobulin test and absent schistocytosis in peripheral blood smear was against the diagnosis of IMHA or hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Final pathological diagnosis on renal biopsy was acute interstitial nephritis with tubular epithelial cytoplasmic vacuolization.
Oxaliplatin is a third-generation platinum compound, which is used in chemotherapy of a wide range of malignancies. Common adverse effects of oxaliplatin are reversible sensory neuropathy, nausea, diarrhea, and mild myelosuppression. 2 Oxaliplatin nephrotoxicity is rare. 1 In a phase I study of oxaliplatin, a WHO grade 2 transient serum creatinine elevation was observed in 4% of cycles. 19 In recent years, there have been multiple reports of different forms of renal toxicity related to oxaliplatin in combination with other agents.3-17 Renal pathologies associated with oxaliplatin use include acute tubular necrosis (ATN),4,6,11 renal tubular acidosis (RTA),9,12,13 IMHA,3,5,8,10,14,15 and HUS/TTP (Table 2).7,16
Previous Case Reports of Oxaliplatin-Related AKI.
Abbreviations: AKI, acute kidney injury; DAT, direct antiglobulin test; F, female; M, male; FOLFOX, modified/FOLinicacid/Fluorouracil/OXaliplatin; LDH, lactate dehydrogenase; ND, not done; IMHA, immune-mediated hemolytic anemia; ATN, acute tubular necrosis; HUS, hemolytic uremic syndrome; TTP, Thrombotic Thrombocytopenic Purpura; RTA, renal tubular acidosis; TMA, thrombotic microangiopathy; XELOX, capecitabine (XELoda®)/ OXaliplatin; ADAMTS13, A disintegrin and metalloproteinase with thrombospondin motifs 13 (von Willebrand factor-cleaving protease)
Mechanisms of oxaliplatin-induced nephrotoxicity are not well understood. Recent findings demonstrate that organic cation transporters (OCT) have a key role in renal accumulation of platinum-based agents. Platinum nephrotoxicity could be explained by renal accumulation through an imbalance between OCTs (especially OCT2) in basolateral membranes of the proximal renal tubules and multidrug and toxin extrusion (MATE, especially MATE2) transport proteins in the brush border membrane of proximal tubules. Oxaliplatin is a substrate for both OCT2 and MATE2. It was suggested that the MATE-mediated efflux of oxaliplatin from tubular cells protects against the nephrotoxicity of oxaliplatin20-22; however, individual variations in the activity of these factors could play a role in renal accumulation of oxaliplatin. The exact cellular and molecular mechanisms underlying how platinum-based agents induce acute tubular injury are not known. Studies have indicated that exposure of tubular cells to cisplatin may activate complex signaling cascades, including inflammatory pathways and vascular and ischemic damage leading to tubular injury and cell death. 21 On the other hand, IMHA and HUS/TTP were reported with oxaliplatin. There are 6 case reports describing oxaliplatin-induced AKI associated with IMHA presenting as acute intravascular hemolytic reaction with fever, chills, back and abdominal pain, jaundice, dark urine, hemoglobinuria, and renal failure.3,5,8,10,14,15 Laboratory data included an increased lactate dehydrogenase level, decreased or absent haptoglobin, increased indirect bilirubin level, and a positive direct Coomb’s test, which is the hallmark of immune-mediated hemolysis. The authors proposed that accumulation of oxaliplatin inducing an immune response could be the possible mechanism of IMHA. Oxaliplatin was etiologically implicated in 2 cases of HUS/TTP with clinical manifestations of AKI.7,16
Tubular epithelial cell vacuolization is induced by ischemic or toxic injury to the kidney and is commonly seen in the context of acute calcineurin inhibitor (cyclosporine or tacrolimus) nephrotoxicity. 23 Renal tubular vacuolization has also been reported after administration of imatinib, desferasirox, cyclophosphamide, immune globulin intravenous (human), and sirolimus. 24 This complication has been reported following the administration of hyperosmotic fluids such as mannitol, inulin, glucose, sucrose, dextran, hydroxyethyl starch, urea, and radiocontrast agents, sometimes referred to as “osmotic nephrosis.” 23 Other studies have described renal tubular cell vacuolization in association with cisplatin use 25 ; however, this reaction had not been reported with oxaliplatin before. Our case is the first report of oxaliplatin-induced renal tubular vacuolization. The renal damage seen in our patient could have been related to the cumulative doses of oxaliplatin.
In summary, oxaliplatin may cause AKI through various mechanisms such as direct renal toxicity or immune-mediated renal damage. In our patient, the presence of jaundice, hematuria, oliguria, increased lactate dehydrogenase, severe anemia, and thrombocytopenia prompted the diagnosis of hemolysis. However, a negative direct antiglobulin test and absent schistocytes in the peripheral blood smear mitigated against the diagnoses of either IMHA or HUS/TTP.
These findings imply that the clinical and some laboratory findings observed in our patient could mimic the IMHA or thrombotic microangiopathy. On the other hand, the absence of hemosiderin deposits in renal biopsy argues strongly against hemolysis being responsible for her AKI. Heightened awareness of this potentially fatal oxaliplatin adverse reaction is warranted. Careful monitoring of renal function as well as changes in hematological parameters is warranted during oxaliplatin-based chemotherapy.
Footnotes
Authors’ Note
The patient consented to the publication of this case report.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.