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      The use of eculizumab in gemcitabine induced thrombotic microangiopathy

      case-report

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          Abstract

          Background

          Thrombotic microangiopathy (TMA) secondary to gemcitabine therapy (GiTMA) is a very rare pathology that carries a poor prognosis, with nearly half of the cases progressing to end stage renal disease. GiTMA is most commonly associated with adenocarcinomas, most notably pancreatic cancers. The mainstay of management is withdrawal of the offending drug and supportive care. Plasmapheresis has a limited role and hemodialysis may help in the management of fluid overload secondary to renal failure. Furthermore, a C5 inhibitor, eculizumab, has been successfully used in the treatment of GiTMA.

          Case presentation

          A 64-year-old Caucasian female with history of pancreatic adenocarcinoma on gemcitabine chemotherapy presented with signs and symptoms of fluid overload and was found to have abnormal kidney function. Her BP was 195/110 mmHg, serum creatinine 4.48 mg/dl, hemoglobin 8.2 g/dl, platelets 53 × 10 3/cmm, lactate dehydrogenase 540 IU/L, and was found to have schistocytes on blood film. A diagnosis of TMA secondary to gemcitabine therapy was suspected. Hemodialysis for volume overload and daily plasmapheresis were initiated. After six days of plasmapheresis, renal function did not improve. Further work up revealed ADAMTS 13 activity >15%, low C3, and stool culture and Shiga-toxin PCR were negative. Renal biopsy was consistent with TMA. Gemcitabine was discontinued, but renal function failed to improve and eculizumab therapy was considered due to suspicion of aHUS. Serum creatinine >2.26 mg/dl and a platelet count of >/= 30 × 10 9/L is highly suggestive of aHUS, while TTP is more likely when creatinine is <2.26 mg/dl and platelet count of <30 × 10 9/L. She received intravenous eculizumab for eight months, which resulted in significant improvement of renal function. Other markers of hemolysis, namely LDH and bilirubin, also rapidly improved following eculizumab therapy. Plasmapheresis and hemodialysis were discontinued after two and eight weeks of initiation respectively.

          Conclusion

          Chemotherapy induced TMA is very rare and requires a high index of clinical suspicion for timely diagnosis. Discontinuation of the offending drug and supportive care is the main stay of treatment; however, eculizumab has been shown to be beneficial in GiTMA. Further research is required to validate this approach.

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          Most cited references24

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          Thrombotic microangiopathies.

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            Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome.

            Atypical hemolytic uremic syndrome (aHUS) in childhood is a rare disease associated with high morbidity and mortality. Most cases progress to end-stage renal failure. In approximately 50% of affected patients, mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway. This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells, particularly in the kidneys. Complement factor H (FH) heterozygosity induces unregulated activation of the membrane attack complex (MAC) C5b-9. Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis. Unfortunately, kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post-transplantation HUS recurrence, particularly in patients with FH mutation. Combined liver-kidney transplantation is also associated with poor outcome, mostly as a result of premature liver failure secondary to uncontrolled complement activation. Eculizumab is a complement C5 antibody that inhibits complement factor 5a (C5a) and the formation of the MAC. Thus, this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation. We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation.
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              A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy.

              Hemolytic uremic syndrome (HUS) is a rare condition that occasionally is reported in cancer patients. Recently it has been observed that gemcitabine rarely may be associated with this condition. The manufacturer's safety database and literature were reviewed for any report regarding gemcitabine associated with renal and hematologic abnormalities. Descriptive analysis was used to examine each case for an association between gemcitabine therapy and HUS and to identify its incidence and risk factors. Through December 31, 1997, 12 cases were identified that fit either the clinical (uremia, microangiopathic hemolytic anemia, and thrombocytopenia) or pathologic (renal biopsy) criteria for HUS. There were 7 males (58%) and 5 females (42%) with a median age of 55.5 years (range, 37-73 years). The median duration of gemcitabine therapy was 5.8 months (range, 3.8-13.1 months). Six patients died, five improved, and one patient's outcome was unknown. Among the six deaths, three patients died of cancer progression, one patient died of an unrelated myocardial infarction, and two patients died of HUS or HUS-related complications. For the five patients who improved, treatment was comprised of dialysis, plasmapheresis, splenectomy, or a combination. Attempts to correlate patient demographics, primary malignancy, and cumulative gemcitabine dose failed to identify consistent risk factors in predisposing patients to HUS. Confounding factors were common, including mitomycin-C and/or 5-fluorouracil exposure, advanced stage tumors, or preexisting renal dysfunction. Based on a patient exposure of 78,800, a crude overall incidence rate of 0.015% (range, 0.008-0.078%) was determined, showing that HUS associated with gemcitabine treatment appears to be rare. Nonetheless, as with other cancer treatments, clinicians should weigh the appropriate risk/benefit ratio in using gemcitabine to treat their patients.
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                Author and article information

                Contributors
                vinodkrishnappa@yahoo.co.in
                mohitgupta1411987@yahoo.co.in
                hshah4@neomed.edu
                adas2@neomed.edu
                tomntan@icloud.com
                rnovak@akronchildrens.org
                330-543-8950 , rraina@akronchildrens.org
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                12 January 2018
                12 January 2018
                2018
                : 19
                : 9
                Affiliations
                [1 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Department of Internal Medicine and Nephrology, , Cleveland Clinic Akron General, ; 1 Akron General Ave, Akron, OH 44307 USA
                [2 ]ISNI 0000 0000 9013 1194, GRID grid.413473.6, Department of Pathology, , Akron Children’s Hospital, ; Akron, OH USA
                [3 ]ISNI 0000 0004 0459 7529, GRID grid.261103.7, Northeast Ohio Medical University, ; Rootstown, OH USA
                [4 ]Department of Nephrology, Weill Cornell Medicine/New York Presbyterian, New York, USA
                Author information
                http://orcid.org/0000-0003-3892-8376
                Article
                812
                10.1186/s12882-018-0812-x
                5767063
                29329518
                daacb519-1be3-4c90-a77a-27080cd8aef6
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 June 2017
                : 1 January 2018
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2018

                Nephrology
                hemolytic uremic syndrome,gemcitabine,thrombotic microangiopathy,renal failure,pancreatic cancer

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