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1
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Barnes DA, Janssen MJ, Yang H, Redegeld FA, Masereeuw R. An adverse outcome pathway for DNA adduct formation leading to kidney failure. Toxicology 2025; 515:154162. [PMID: 40268266 DOI: 10.1016/j.tox.2025.154162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/11/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
An Adverse Outcome Pathway (AOP) is a conceptual framework in toxicology and risk assessment that outlines the series of events from a chemical's molecular interaction to the resulting adverse health effect. This framework offers a structured approach to organizing biological knowledge, making it especially useful for understanding the mechanisms through which chemicals cause harm. Following a comprehensive analysis of the literature, an AOP was elucidated for key events linking DNA adduct formation, caused by compounds such as platinum anticancer drugs, to tubular necrosis, resulting in kidney failure. Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer. The hydrolysis of platinum anticancer agents post-cellular uptake yields electrophilic intermediates that covalently bind to nucleophilic sites on DNA to form adducts that represent the molecular initiating event. When DNA repair mechanisms become unbalanced, the nephrotoxic response following the formation of DNA adducts leads to DNA damage and mitochondrial dysfunction. These events promote the generation and release of reaction oxygen species (ROS) to induce oxidative stress, causing cell death and inflammation. Upon detachment from the basement membrane, these compromised cells are subsequently deposited in the tubular lumen. Tubular obstruction and inflammatory responses to proximal tubule insult can lead to secondary toxicity and tubular necrosis, further exacerbating kidney injury and precipitating a progressive decline of renal function, finally resulting in kidney failure.
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Affiliation(s)
- D A Barnes
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | - M J Janssen
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | | | - F A Redegeld
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | - R Masereeuw
- Utrecht University, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.
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2
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Lyrio RMDC, Rocha BRA, Corrêa ALRM, Mascarenhas MGS, Santos FL, Maia RDH, Segundo LB, de Almeida PAA, Moreira CMO, Sassi RH. Chemotherapy-induced acute kidney injury: epidemiology, pathophysiology, and therapeutic approaches. FRONTIERS IN NEPHROLOGY 2024; 4:1436896. [PMID: 39185276 PMCID: PMC11341478 DOI: 10.3389/fneph.2024.1436896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/22/2024] [Indexed: 08/27/2024]
Abstract
Despite significant advancements in oncology, conventional chemotherapy remains the primary treatment for diverse malignancies. Acute kidney injury (AKI) stands out as one of the most prevalent and severe adverse effects associated with these cytotoxic agents. While platinum compounds are well-known for their nephrotoxic potential, other drugs including antimetabolites, alkylating agents, and antitumor antibiotics are also associated. The onset of AKI poses substantial risks, including heightened morbidity and mortality rates, prolonged hospital stays, treatment interruptions, and the need for renal replacement therapy, all of which impede optimal patient care. Various proactive measures, such as aggressive hydration and diuresis, have been identified as potential strategies to mitigate AKI; however, preventing its occurrence during chemotherapy remains challenging. Additionally, several factors, including intravascular volume depletion, sepsis, exposure to other nephrotoxic agents, tumor lysis syndrome, and direct damage from cancer's pathophysiology, frequently contribute to or exacerbate kidney injury. This article aims to comprehensively review the epidemiology, mechanisms of injury, diagnosis, treatment options, and prevention strategies for AKI induced by conventional chemotherapy.
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Affiliation(s)
| | | | | | | | - Felipe Luz Santos
- Department of Medicine, Universidade Salvador (UNIFACS), Salvador, Brazil
| | | | | | | | | | - Rafael Hennemann Sassi
- Hematology Department, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
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3
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Gupta S, Portales-Castillo I, Daher A, Kitchlu A. Conventional Chemotherapy Nephrotoxicity. Adv Chronic Kidney Dis 2021; 28:402-414.e1. [PMID: 35190107 DOI: 10.1053/j.ackd.2021.08.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 12/27/2022]
Abstract
Conventional chemotherapies remain the mainstay of treatment for many malignancies. Kidney complications of these therapies are not infrequent and may have serious implications for future kidney function, cancer treatment options, eligibility for clinical trials, and overall survival. Kidney adverse effects may include acute kidney injury (via tubular injury, tubulointerstitial nephritis, glomerular disease and thrombotic microangiopathy), long-term kidney function loss and CKD, and electrolyte disturbances. In this review, we summarize the kidney complications of conventional forms of chemotherapy and, where possible, provide estimates of incidence, and identify risk factors and strategies for kidney risk mitigation. In addition, we provide recommendations regarding kidney dose modifications, recognizing that these adjustments may be limited by available supporting pharmacokinetic and clinical outcomes data. We discuss management strategies for kidney adverse effects associated with these therapies with drug-specific recommendations. We focus on frequently used anticancer agents with established kidney complications, including platinum-based chemotherapies (cisplatin, carboplatin, oxaliplatin), cyclophosphamide, gemcitabine, ifosfamide, methotrexate and pemetrexed, among others.
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4
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Gal S, Noa M, Ofer M, Naama H, Ben B, Einat SS. Oxaliplatin immune-mediated thrombocytopenia: Is there a role for premedication or desensitization? Br J Clin Pharmacol 2021; 88:842-845. [PMID: 34237795 DOI: 10.1111/bcp.14974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 06/20/2021] [Accepted: 06/23/2021] [Indexed: 11/30/2022] Open
Abstract
Oxaliplatin is a common chemotherapy agent that is used in the treatment of multiple solid malignancies. Immune-mediated thrombocytopenia is a rare and potentially life-threatening adverse effect of oxaliplatin that is characterized by severe thrombocytopenia, which may be accompanied by overt bleeding. This adverse effect is probably mediated via anti-platelet antibodies that become reactive in the presence of oxaliplatin. Due to its rarity and severity, information is scarce regarding the effect of desensitization or attempts at rechallenge after prolonged withdrawal of oxaliplatin. This short report describes 3 cases of oxaliplatin immune-mediated thrombocytopenia, including a case occurring under desensitization protocol and a case of recurrence after a prolo nged withdrawal. All 3 patients are female, have prolonged exposures to oxaliplatin and were all treated for metastatic colorectal cancer. Physicians should be aware of oxaliplatin immune-mediated thrombocytopenia as symptoms may appear rapidly. Oxaliplatin should be permanently discontinued for patients experiencing this adverse effect, as recurrence is highly likely even in the setting of desensitization.
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Affiliation(s)
- Strauss Gal
- Department of Oncology, Sheba Medical Center, Israel
| | - Markovits Noa
- Department of Oncology, Sheba Medical Center, Israel
| | - Margalit Ofer
- Department of Oncology, Sheba Medical Center, Israel
| | - Halpern Naama
- Department of Oncology, Sheba Medical Center, Israel
| | - Boursi Ben
- Department of Oncology, Sheba Medical Center, Israel
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5
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Shi XQ, Zhu ZH, Yue SJ, Tang YP, Chen YY, Pu ZJ, Tao HJ, Zhou GS, Duan JA. Studies on blood enrichment and anti-tumor effects of combined Danggui Buxue Decoction, Fe and rhEPO based on colon cancer-related anemia model and gut microbiota modulation. Chin J Nat Med 2021; 19:422-431. [PMID: 34092293 DOI: 10.1016/s1875-5364(21)60041-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Indexed: 11/17/2022]
Abstract
Colon cancer-related anemia (CCRA) is mainly caused by systemic inflammation, intestinal bleeding, iron deficiency and chemotherapy-induced myelosuppression in colon cancer. However, the best therapeutic schedule and related mechanism on CCRA were still uncertain. Studies on blood enrichment and anti-tumor effects of combined Danggui Buxue Decoction (DBD), Fe and rhEPO based on CCRA and gut microbiota modulation were conducted in this paper. Here, CCRA model was successfully induced by subcutaneous inoculation of CT-26 and i.p. oxaliplatin, rhEPO + DBD high dosage + Fe (EDF) and rhEPO + DBD high dosage (ED) groups had the best blood enrichment effect. Attractively, EDF group also showed antitumor activity. The sequencing results of gut microbiota showed that compared to P group, the relative abundances of Lachnospiraceae and opportunistic pathogen (Odoribacter) in ED and EDF groups were decreased. Interestingly, EDF also decreased the relative abundances of cancer-related bacteria (Helicobacter, Lactococcus, Alloprevotella) and imbalance-inducing bacteria (Escherichia-Shigella and Parabacteroides) and increased the relative abundances of butyrate-producing bacteria (Ruminococcaceae_UCG-014), however, ED showed the opposite effects to EDF, this might be the reason of the smaller tumor volume in EDF group. Our findings proposed the best treatment combination of DBD, rhEPO and Fe in CCRA and provided theoretical basis and literature reference for CCRA-induced intestinal flora disorder and the regulatory mechanism of EDF.
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Affiliation(s)
- Xu-Qin Shi
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhen-Hua Zhu
- Institute of Mental Health, Suzhou Psychiatric Hospital, Soochow University Affiliated Guangji Hospital, Suzhou 215100, China
| | - Shi-Jun Yue
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, China
| | - Yu-Ping Tang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, China.
| | - Yan-Yan Chen
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, China
| | - Zong-Jin Pu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Hui-Juan Tao
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Gui-Sheng Zhou
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jin-Ao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Bridoux F, Cockwell P, Glezerman I, Gutgarts V, Hogan JJ, Jhaveri KD, Joly F, Nasr SH, Sawinski D, Leung N. Kidney injury and disease in patients with haematological malignancies. Nat Rev Nephrol 2021; 17:386-401. [PMID: 33785910 DOI: 10.1038/s41581-021-00405-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Acute kidney injury (AKI) is common in patients with cancer, especially in those with haematological malignancies. Kidney injury might be a direct consequence of the underlying haematological condition. For example, in the case of lymphoma infiltration or extramedullary haematopoiesis, it might be caused by a tumour product; in the case of cast nephropathy it might be due to the presence of monoclonal immunoglobulin; or it might result from tumour complications, such as hypercalcaemia. Kidney injury might also be caused by cancer treatment, as many chemotherapeutic agents are nephrotoxic. High-intensity treatments, such as high-dose chemotherapy followed by haematopoietic stem cell transplantation, not only increase the risk of infection but can also cause AKI through various mechanisms, including viral nephropathies, engraftment syndrome and sinusoidal obstruction syndrome. Some conditions, such as thrombotic microangiopathy, might also result directly from the haematological condition or the treatment. Novel immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cell therapy, can also be nephrotoxic. As new therapies for haematological malignancies with increased anti-tumour efficacy and reduced toxicity are developed, the number of patients receiving these treatments will increase. Clinicians must gain a good understanding of the different mechanisms of kidney injury associated with cancer to better care for these patients.
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Affiliation(s)
- Frank Bridoux
- Department of Nephrology, and Centre d'Investigation Clinique (CIC INSERM 1402), Centre Hospitalier Universitaire et Université de Poitiers, Poitiers, France.,CNRS, UMR7276, Limoges, France.,Centre de référence Amylose AL et autres maladies par dépôt d'immunoglobulines monoclonales, Poitiers, France
| | - Paul Cockwell
- Department of Nephrology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Ilya Glezerman
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Victoria Gutgarts
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Jonathan J Hogan
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, NY, USA
| | - Florent Joly
- Department of Nephrology, and Centre d'Investigation Clinique (CIC INSERM 1402), Centre Hospitalier Universitaire et Université de Poitiers, Poitiers, France
| | - Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Deirdre Sawinski
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Nelson Leung
- Division of Nephrology and Hypertension, Division of Hematology, Mayo Clinic, Rochester, MN, USA.
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7
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Oxaliplatin-Induced Evans Syndrome: A Possible Dual Mechanism. Clin Colorectal Cancer 2020; 19:57-60. [DOI: 10.1016/j.clcc.2019.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 10/15/2019] [Accepted: 11/19/2019] [Indexed: 01/23/2023]
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8
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Acute Immune-Mediated Thrombocytopenia due to Oxaliplatin and Irinotecan Therapy. Case Rep Oncol Med 2019; 2019:4314797. [PMID: 31781443 PMCID: PMC6875012 DOI: 10.1155/2019/4314797] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 09/26/2019] [Accepted: 10/12/2019] [Indexed: 12/13/2022] Open
Abstract
We describe a case of a 63-year-old woman with advanced colon cancer and liver metastases who was treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and cetuximab chemotherapy. She tolerated 13 cycles of chemotherapy without any significant hematological side effects, but after the 14th cycle, she developed melena and was admitted for severe thrombocytopenia. After supportive care, the platelet counts rapidly improved to 76,000/μL. Upon initiation of FOLFIRI and cetuximab chemotherapy, she again developed rectal bleeding and severe thrombocytopenia with a platelet count of 6000/μL. Lab testing was positive for oxaliplatin and irinotecan drug-dependent platelet antibodies on flow cytometry assay. Drug-induced thrombocytopenia (DITP) is associated with several classes of drugs with several proposed underlying mechanisms. Prospective studies are needed to further address different mechanisms of drug-induced thrombocytopenia.
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9
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Garciaz S, Oziel-Taieb S, Dermeche S, Ries P, Vessaud J, Raoul JL. Acute Immune Hematological Complication of Oxaliplatin. A Series of 3 Cases. TUMORI JOURNAL 2018. [DOI: 10.1177/1430.15831] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Sylvain Garciaz
- Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France
| | | | - Slimane Dermeche
- Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France
| | - Pauline Ries
- Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France
| | - Julie Vessaud
- Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France
| | - Jean-Luc Raoul
- Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France
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10
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Phull P, Quillen K, Hartshorn KL. Acute Oxaliplatin-induced Hemolytic Anemia, Thrombocytopenia, and Renal Failure: Case Report and a Literature Review. Clin Colorectal Cancer 2016; 16:S1533-0028(16)30259-6. [PMID: 27989485 DOI: 10.1016/j.clcc.2016.11.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/05/2016] [Accepted: 11/14/2016] [Indexed: 12/27/2022]
Affiliation(s)
- Pooja Phull
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Karen Quillen
- Section of Hematology Oncology, Boston University School of Medicine, Boston, MA
| | - Kevan L Hartshorn
- Section of Hematology Oncology, Boston University School of Medicine, Boston, MA.
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11
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Bencardino K, Mauri G, Amatu A, Tosi F, Bonazzina E, Palmeri L, Querques M, Ravera F, Menegotto A, Boiani E, Sartore-Bianchi A, Siena S. Oxaliplatin Immune-Induced Syndrome Occurs With Cumulative Administration and Rechallenge: Single Institution Series and Systematic Review Study. Clin Colorectal Cancer 2016; 15:213-21. [DOI: 10.1016/j.clcc.2016.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 12/22/2015] [Accepted: 02/03/2016] [Indexed: 01/27/2023]
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12
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Joybari AY, Sarbaz S, Azadeh P, Mirafsharieh SA, Rahbari A, Farasatinasab M, Mokhtari M. Oxaliplatin-induced renal tubular vacuolization. Ann Pharmacother 2014; 48:796-800. [PMID: 24615628 DOI: 10.1177/1060028014526160] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE Chemotherapy with oxaliplatin is used for a wide range of malignancies. Unlike other platinum derivatives, oxaliplatin has less nephrotoxicity. However, in recent years, there have been multiple reports of different forms of renal toxicity related to this agent. CASE SUMMARY A 40-year-old woman with colon adenocarcinoma developed jaundice, hematuria, and oliguria after the 36th cycle of oxaliplatin chemotherapy. Laboratory data revealed severe anemia, thrombocytopenia, increased creatinine, indirect hyperbilirubinemia, and high lactate dehydrogenase. A negative direct antiglobulin test and presence of <1% schistocytes in the peripheral blood smear stood against the diagnosis of immune-mediated hemolytic anemia or hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Renal biopsy was consistent with interstitial nephritis with tubular vacuolization in favor of drug-induced renal injury. Based on the Naranjo Probability Scale, the likelihood of oxaliplatin-induced renal injury in this case was probable. DISCUSSION 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. CONCLUSIONS Oxaliplatin can induce various forms of nephrotoxicity such as renal tubular vacuolization, acute tubular necrosis, renal tubular acidosis, and acute kidney injury secondary to hematological toxicity. Monitoring for renal function abnormalities and hemolysis should be considered during oxaliplatin-based chemotherapy.
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13
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Forcello NP, Khubchandani S, Patel SJ, Brahaj D. Oxaliplatin-induced immune-mediated cytopenias: a case report and literature review. J Oncol Pharm Pract 2014; 21:148-56. [PMID: 24500808 DOI: 10.1177/1078155213520262] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Oxaliplatin is a third-generation platinum antineoplastic agent that commonly causes diarrhea, nausea, vomiting, myelosuppression, and peripheral neuropathy. Less common adverse effects that are increasingly being reported include acute immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia. Here, we report a patient case of suspected oxaliplatin-induced immune-mediated thrombocytopenia and a thorough literature evaluation of acute oxaliplatin-induced immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia that has yet to be reported until now. There have been 39 previously published reports of these cytopenic events with a median number of 16 treatment cycles prior to presentation. Patients experiencing unusual signs and symptoms such as chills, rigors, fever, back pain, abdominal pain, ecchymosis, hematemesis, hematuria, dark urine, hematochezia, petechiae, epistaxis, or mental status changes during or shortly after an oxaliplatin infusion should have complete blood counts ordered and evaluated promptly.
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Affiliation(s)
| | - Sapna Khubchandani
- Department of Hematology and Oncology, Bristol Hospital, Bristol, CT, USA
| | - Shrina J Patel
- School of Pharmacy, University of Saint Joseph, Hartford, CT, USA
| | - Driola Brahaj
- Department of Hematology and Oncology, Bristol Hospital, Bristol, CT, USA
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14
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Filewod N, Lipman ML. Severe acute tubular necrosis observed subsequent to oxaliplatin administration. Clin Kidney J 2013; 7:68-70. [PMID: 25859355 PMCID: PMC4389161 DOI: 10.1093/ckj/sft148] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 11/19/2013] [Indexed: 12/15/2022] Open
Abstract
A 67-year-old man known for metastatic colon cancer received treatment with oxaliplatin and developed severe acute kidney injury requiring dialysis. Renal biopsy revealed severe acute tubular necrosis. Acute kidney injury is a rare but severe adverse effect of oxaliplatin administration.
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Affiliation(s)
- Niall Filewod
- Department of Medicine , McGill University Health Centre , Montreal, QC , Canada
| | - Mark L Lipman
- Division of Nephrology, Department of Medicine , Jewish General Hospital , Montreal, QC , Canada
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15
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Sakhri L, Mennecier B, Quoix A. [Hemolytic anemia under erlotinib treatment]. REVUE DE PNEUMOLOGIE CLINIQUE 2013; 69:345-350. [PMID: 24183296 DOI: 10.1016/j.pneumo.2013.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Revised: 06/08/2013] [Accepted: 06/15/2013] [Indexed: 06/02/2023]
Abstract
Erlotinib is a tyrosine kinase inhibitor widely prescribed of which the most common sides effects are grade I or II rash and diarrhea. We report two cases of hemolytic anemia (HA) induced by erlotinib. Our two patients were treated with erlotinib after a prior line of systemic platinum-doublet therapy for metastatic non-small cell lung cancer. Both patients presented, shortly after starting treatment with erlotinib, an HA which was fatal for one of them. To our knowledge, this major side effect of erlotinib has not been reported in the literature. We will try through this article to make a literature review of the most important side effects of erlotinib and we will also focus on the HA induced by other molecules used in oncology.
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Affiliation(s)
- L Sakhri
- Service de pneumologie, pôle de cancérologie, médecine aiguë et communautaire, CHU Michallon, boulevard de la Chantourne, BP 217, 38043 Grenoble cedex 9, France.
| | - B Mennecier
- Service de pneumologie, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg cedex, France
| | - A Quoix
- Service de pneumologie, nouvel hôpital civil, 1, place de l'Hôpital, BP 426, 67091 Strasbourg cedex, France
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16
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Garcia SS, Atkins JT, Falchook GS, Tsimberidou AM, Hong DS, Trivedi MV, Kurzrock R. Transient severe hyperbilirubinemia after hepatic arterial infusion of oxaliplatin in patients with liver metastases. Cancer Chemother Pharmacol 2013; 72:1265-71. [PMID: 24101145 DOI: 10.1007/s00280-013-2302-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 09/23/2013] [Indexed: 01/17/2023]
Abstract
PURPOSE We have observed severe, but rapidly reversible, hyperbilirubinemia in patients receiving hepatic arterial infusion (HAI) of oxaliplatin. We performed a retrospective analysis to characterize this unusual phenomenon. METHODS We reviewed the electronic medical records of 113 consecutive patients receiving HAI oxaliplatin to describe the associated hyperbilirubinemia. RESULTS Four of 113 patients (3.5 %) presented with transient, severe (grade 3/4) hyperbilirubinemia post-HAI oxaliplatin. Peak levels of total bilirubin within 10-16 h of starting HAI oxaliplatin were 4.6, 12.2, 12.8, and 21.2 mg/dL and declined rapidly (within 24 after stopping treatment). One out of four patients experienced severe abdominal pain, and another patient had an infusion reaction (hypertension and hypoxemia) that reversed after discontinuation of infusion. Total bilirubin was predominantly direct. No significant decline in hemoglobin or increase in alkaline phosphatase occurred. Increase in liver transaminases post-infusion was mild to moderate (grades 1-3) and was seen after HAI oxaliplatin regardless of the emerged hyperbilirubinemia. CONCLUSIONS Severe hyperbilirubinemia is a rare but rapidly reversible adverse effect of HAI oxaliplatin and may be accompanied by an abdominal pain syndrome or infusion reaction. Treating physicians should be aware for the potential of this reaction. The mechanism of this unusual reaction merits further investigation.
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Affiliation(s)
- Sean S Garcia
- Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX, 77030, USA
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Niu J, Mims MP. Oxaliplatin-Induced Thrombotic Thrombocytopenic Purpura: Case Report and Literature Review. J Clin Oncol 2012; 30:e312-4. [DOI: 10.1200/jco.2012.42.5082] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Jiaxin Niu
- Cancer Treatment Centers of America at Western Regional Medical Center, Goodyear, AZ
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18
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Jardim DL, Rodrigues CA, Novis YAS, Rocha VG, Hoff PM. Oxaliplatin-related thrombocytopenia. Ann Oncol 2012; 23:1937-1942. [PMID: 22534771 DOI: 10.1093/annonc/mds074] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023] Open
Abstract
Oxaliplatin is a third generation platinum compound that inhibits DNA synthesis, mainly through intrastrandal cross-links in DNA. Most of the experience with the clinical use of this drug is derived from colorectal cancer but it is also used in other tumor types such as ovary, breast, liver and non-Hodgkin's lymphoma. Thrombocytopenia is a frequent toxicity seen during oxaliplatin treatment, occurring at any grade in up to 70% of patients and leading to delays or even discontinuation of the chemotherapy. Although myelossupression is recognized as the main cause of oxaliplatin-related thrombocytopenia, new mechanisms for this side-effect have emerged, including splenic sequestration of platelets related to oxaliplatin-induced liver damage and immune thrombocytopenia. These new pathophysiology pathways have different clinical presentations and evolution and may need specific therapeutic maneuvers. This article attempts to review this topic and provides useful clinical information for the management of oxaliplatin-related thrombocytopenia.
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Affiliation(s)
- D L Jardim
- Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo.
| | - C A Rodrigues
- Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo; Department of Clinical and Experimental Hematology, Universidade Federal do Estado de Sao Paulo, Sao Paulo
| | - Y A S Novis
- Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo
| | - V G Rocha
- Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo; Department of Radiology and Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - P M Hoff
- Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo; Department of Radiology and Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
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Kurian S, Macintyre J, Mushtaq M, Rocha-Lima CM, Ahn Y. Oxaliplatin induced disseminated intravascular coagulation: A case report and review of literature. World J Gastrointest Oncol 2012; 4:181-3. [PMID: 22844549 PMCID: PMC3406283 DOI: 10.4251/wjgo.v4.i7.181] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 11/01/2011] [Accepted: 11/15/2011] [Indexed: 02/05/2023] Open
Abstract
Oxaliplatin in combination with a fluoropyrimide is a treatment option for colorectal cancer patients in the adjuvant and metastatic settings. Very few hematological emergencies have been reported associated with Oxaliplatin. These include autoimmune hemolytic anemia, thrombocytopenia and pancytopenia. We present a case report of a patient who developed hematuria and disseminated intravascular coagulation while receiving the second cycle of FOLFOX and bevacizumab for metastatic colon cancer.
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Affiliation(s)
- Shweta Kurian
- Shweta Kurian, Jessica Macintyre, Muzammil Mushtaq, Caio Max Rocha-Lima, Yeon Ahn, Division of Hematology Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, United States
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Ito I, Ito Y, Mizuno M, Suzuki Y, Yasuda K, Ozaki T, Kosugi T, Yasuda Y, Sato W, Tsuboi N, Maruyama S, Imai E, Matsuo S. A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin. Clin Exp Nephrol 2012; 16:490-4. [DOI: 10.1007/s10157-012-0620-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Accepted: 02/29/2012] [Indexed: 12/27/2022]
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Teng CJ, Hsieh YY, Chen KW, Chao TC, Tzeng CH, Wang WS. Sudden-onset pancytopenia with intracranial hemorrhage after oxaliplatin treatment: a case report and literature review. Jpn J Clin Oncol 2010; 41:125-9. [PMID: 20826449 DOI: 10.1093/jjco/hyq162] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Oxaliplatin is a third-generation platinum compound and has been widely employed in the treatment of colorectal cancer. Despite its good efficacy, it is reported to induce immune-mediated cytopenia. We report the case of a 78-year-old male patient who experienced acute pancytopenia along with coagulopathy and intracranial hemorrhage after his 17th course of oxaliplatin. This condition appeared immediately after completion of oxaliplatin infusion, and was persistent despite aggressive transfusion and treatment with granulocyte colony-stimulating factor. The patient died 72 h after the administration of oxaliplatin. The only preceding symptom was chills 30 min after initiation of oxaliplatin, although steroid was given as premedication. We review the literature describing oxaliplatin-induced cytopenia, and discuss the manifestation, immune mechanism and treatment of this condition. We conclude that any symptoms that occur during infusion of oxaliplatin should not be overlooked but should be taken seriously as they may represent 'a little spark that kindles a great fire', and that steroids may provide an effective treatment for oxaliplatin-induced cytopenia. However, a major complication in our patient may still happen. Further studies for the mechanism and the predictive markers of oxaliplatin-induced cytopenia are worthy.
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Affiliation(s)
- Chung-Jen Teng
- Division of Oncology and Hematology, Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan
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Bautista MA, Stevens WT, Chen CS, Curtis BR, Aster RH, Hsueh CT. Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature. J Hematol Oncol 2010; 3:12. [PMID: 20346128 PMCID: PMC2859393 DOI: 10.1186/1756-8722-3-12] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Accepted: 03/26/2010] [Indexed: 11/18/2022] Open
Abstract
Background Oxaliplatin is a platinum compound used in the treatment of gastrointestinal malignancies, including colorectal cancer. The incidence of hypersensitivity reaction in patients receiving oxaliplatin is approximately 15%, with severe reaction (grade 3 and 4) occurring in 2% of patients. Case presentation We report two patients with metastatic colorectal cancer who developed de novo hypersensitivity reaction and acute thrombocytopenia after oxaliplatin infusion. Both patients had oxaliplatin treatment several years before and exhibited hypersensitivity on the third dose of oxaliplatin in recent treatment. Oxaliplatin was discontinued when clinical reaction was identified. Both patients were confirmed to have strong oxaliplatin-induced IgG platelet-reactive antibodies. Both patients' thrombocytopenia resolved within two weeks after discontinuation of oxaliplatin. One patient had disease stabilization lasting for three months without chemotherapy. Both patients subsequently received other chemotherapeutic agents without evidence of hypersensitivity reaction or immune-mediated thrombocytopenia. Conclusion We recommend vigilant monitoring of complete blood count and signs and symptoms of bleeding after the occurrence of oxaliplatin-induced hypersensitivity to avoid serious complications of immune-mediated thrombocytopenia.
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Affiliation(s)
- Marnelli A Bautista
- Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, CA 92354, USA
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James E, Podoltsev N, Salehi E, Curtis BR, Saif MW. Oxaliplatin-Induced Immune Thrombocytopenia: Another Cumulative Dose-Dependent Side Effect? Clin Colorectal Cancer 2009; 8:220-4. [DOI: 10.3816/ccc.2009.n.037] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Santodirocco M, Lombardi V, Fesce C, Palumbo G, Capalbo S, Landriscina M. Life-threatening oxaliplatin-induced acute thrombocytopenia, hemolysis and bleeding: a case report. Acta Oncol 2009; 47:1602-4. [PMID: 18607839 DOI: 10.1080/02841860801978913] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Arndt P, Garratty G, Isaak E, Bolger M, Lu Q. Positive direct and indirect antiglobulin tests associated with oxaliplatin can be due to drug antibody and/or drug-induced nonimmunologic protein adsorption. Transfusion 2009; 49:711-8. [DOI: 10.1111/j.1537-2995.2008.02028.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Compostella A, Pasetto LM, Ghiotto C, Stefani M, Monfardini S. Oxaliplatin-Induced Haemolytic Anaemia: A Case Report. Clin Med Oncol 2007. [DOI: 10.1177/117955490700100003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Oxaliplatin plus 5Fluorouracil (5FU) and leucovorin (LV) is the standard treatment of metastatic colorectal cancer (CRC). We describe a rare clinical case of acute renal failure probably oxaliplatin-related at one day from the end of the palliative treatment. A 36 year-old woman developed a stage I CRC. Five months later a liver lesion was detected and treated with FOLFOX4 schedule. Because of progression the patient underwent surgery and she repeated the Oxaliplatin-based therapy for more than one cycle. After many months of therapy, on the second day, the patient noticed urine discoloration. Immediate urinanalysis demonstrated haemoglobinuria. The patient's complete blood count exhibited signs consistent with acute hemolysis, neutrophilic leucocytosis, thrombocytopenia and acute renal failure. She was treated with blood transfusion and hemodialysis and she was managed conservatively with monitored intravenous hydration and loop diuretics. The patient gradually recovered and the results of successive hematological and biochemical tests confirmed the improvement of her condition but a cardiologic evaluation showed a iatrogenic depressed systolic function (ejection fraction of 40%).
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Affiliation(s)
- A Compostella
- Istituto Oncologico Veneto, IRCCS: Medical Oncology 2nd, Via Gattamelata 64, 35128 Padova, Italy
| | - LM Pasetto
- Istituto Oncologico Veneto, IRCCS: Medical Oncology 2nd, Via Gattamelata 64, 35128 Padova, Italy
| | - C Ghiotto
- Istituto Oncologico Veneto, IRCCS: Medical Oncology 2nd, Via Gattamelata 64, 35128 Padova, Italy
| | - M Stefani
- Istituto Oncologico Veneto, IRCCS: Medical Oncology 2nd, Via Gattamelata 64, 35128 Padova, Italy
| | - S Monfardini
- Istituto Oncologico Veneto, IRCCS: Medical Oncology 2nd, Via Gattamelata 64, 35128 Padova, Italy
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Abstract
PURPOSE OF REVIEW This article reviews recent publications that bear on the evidential basis for therapeutic apheresis in diseases in which hemolytic anemia is a prominent feature. RECENT FINDINGS Therapeutic plasma exchange continues to be reported sporadically in severe autoimmune hemolytic anemia, with inconsistent results. Autoimmune deficiency of ADAMTS13 has provided a compelling rationale for therapeutic plasma exchange in some patients with thrombotic thrombocytopenic purpura; conversely such deficiency is consistently absent in certain clinically similar syndromes for which therapeutic plasma exchange is not or may not be beneficial. Refinements in assays for ADAMTS13 should further clarify its role in idiopathic thrombotic thrombocytopenic purpura. Oral iron chelators have shown promise in recent trials in chronically transfused patients with sickle cell disease and may provide an alternative to red cell exchange to prevent iron overload. SUMMARY The proper role of therapeutic plasma exchange in the treatment of autoimmune hemolytic anemia remains uncertain. Therapeutic plasma exchange continues to be indicated for idiopathic thrombotic thrombocytopenic purpura regardless of ADAMTS13 levels, but more accessible and physiological ADAMTS13 assays may raise questions about the rationale for and value of plasma exchange in ADAMTS13 nondeficient patients. Oral iron chelation may obviate the need for red cell exchange as a means to prevent iron overload in chronically transfused patients with sickle cell disease.
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Affiliation(s)
- Bruce C McLeod
- Blood Center, Rush University Medical Center, Chicago, Illinois 60612, USA.
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