Hemolytic uremic syndrome due to gemcitabine in a young woman with cholangiocarcinoma

A gencitabina é um fármaco utilizado no tratamento de vários tipos de neoplasias malignas. Há poucas descrições de associação entre a droga e a síndrome hemolítico-urêmica (SHU), apesar de os pacientes em questão terem ido a óbito em pelo menos 50% dos casos. O presente artigo relata o caso de uma paciente com 25 anos de idade em remissão diagnosticada com colangiocarcinoma que apresentou anemia hemolítica microangiopática acompanhada de insuficiência renal aguda anúrica após cinco ciclos de quimioterapia com gencitabina; as manifestações eram condizentes com SHU causada pelos efeitos colaterais do medicamento. A administração de gencitabina foi interrompida, e a paciente foi tratada com hemodiálise, transfusões de sangue, trocas de plasma, corticosteroides, doxiciclina e rituximabe. Foi atingido um desfecho favorável; mais especificamente, a hemólise foi controlada e a função renal foi plenamente restabelecida. Resumo


IntRoductIon
Thrombotic microangiopathies (TMAs) are a series of disorders characterized by the presence of non-immune hemolytic anemia, thrombocytopenia, and multiple organ failure, with frequent renal and/ or neurological damage. 1 Differential diagnoses of TMAs are extremely wideranging.TMAs may be associated with ADAMTS-13 deficiency, which would result in a diagnosis of thrombotic thrombocytopenic purpura (TTP); 2 intestinal infection by enterobacteria that produce Shiga-toxin, which would lead to a diagnosis of typical hemolytic uremic syndrome (tHUS); 3 or complement disorders that cause atypical hemolytic uremic syndrome (aHUS). 4In addition, TMAs may be initiated or triggered by multiple secondary causes, including autoimmune diseases, metabolic diseases, neoplastic diseases, infectious diseases, cardiovascular diseases, and drug-related effects. 1 The drugs most frequently associated with TMAs include chemotherapeutic agents such as mitomycin C, cisplatin, 5-fluorouracil, carboplatin, and gemcitabine. 1,5The early recognition of drug-associated TMAs is important because it allows for the immediate suspension of treatment with the causal agent and the establishment of timely support measures to curb damage-causing pathophysiological processes; this issue is particularly critical given the extremely poor short-and long-term prognoses of these disorders. 5,6he following section describes the case of a young woman diagnosed with cholangiocarcinoma in remission who developed hemolytic uremic syndrome (HUS) during the fifth cycle of gemcitabine chemotherapy.

clInIcAl cAse
The examined case involved a 25-year-old woman with a history of intrahepatic cholangiocarcinoma, which was diagnosed 18 months prior to this report.Her treatment included a hepatectomy and 5 cycles of chemotherapy with gemcitabine.She was admitted due to the recent onset of the following symptoms: malaise, a throbbing headache, progressive lower limb edema, oliguria and dyspnea.During physical examination, the patient was pale; petechiae and anasarca were observed.Laboratory tests revealed pancytopenia, elevated lactate dehydrogenase (LDH) levels, schistocytosis and acute renal failure (Table 1).
An immunological profile was negative except for hypocomplementemia.Shiga toxin tests were not requested because the patient did not present with diarrhea.Images of the patient's abdomen and skull revealed no abnormalities.Given these findings, HUS resulting from gemcitabine-induced TMA was diagnosed.
The patient was treated with daily plasma exchanges and renal replacement therapy.A total of 14 plasma exchanges were performed, with partial response.The patient concomitantly received 1 mg/kg of prednisone per day, 100 mg of doxycycline every 12 hours and 2 doses of rituximab (1 g every two weeks).
After the second rituximab dose a hemolysis was controlled, although oliguric acute renal failure persisted.Therefore, a renal biopsy was obtained; this biopsy confirmed the presence of active TMA (Figure 1).Eight weeks after the onset of the patient's clinical condition, her renal function completely recovered; no relapse was observed at 12-month follow-up (Figure 2).

dIscussIon
We report on the case of a patient with cholangiocarcinoma in remission who received treatment with gemcitabine, developed severe TMA associated with this medication, and exhibited a successful response to treatment.
Gemcitabine is used to treat certain malignant conditions, including pancreatic cancer, cholangiocarcinoma, hepatocarcinoma, lymphoma, bladder cancer, and breast câncer. 5In 1994, Casper et al. first described an association between gemcitabine and HUS in a study of a group of pancreatic adenocarcinoma patients who received chemotherapy. 6Subsequently, gemcitabine--associated HUS has been described in the treatment of many malignant neoplastic conditions; in particular, this condition exhibits incidences ranging from 0.015% to 2.2%, 7,8 although these values are underestimates due to the underreporting of HUS cases. 5 The exact mechanisms by which gemcitabine causes HUS is unclear; among the various hypotheses, the most prominent theory is that direct damage to endothelial cells leads to cellular edema, the separation of the endothelium from its basement membrane, and the formation of microthrombi as a side effect of the activation of inflammatory, coagulation, growth, platelet activation, prothrombotic, and chemotactic factors. 9nother theory, which is focused on the immune system, suggests that circulating complexes form that trigger platelet aggregation and deposition in areas of endothelial damage in the renal microcirculation or that antibodies against self-antigens form after gemcitabine-induced endothelial damage. 10Certain authors have proposed that antibodies against the ADAMTS-13 enzyme are produced; as a result, large von Willebrand multimers cannot be cleaved, leading to platelet activation and capillary thrombosis. 1,9one of these theories have been confirmed.However, it has been demonstrated that stopping the administration of gemcitabine can lead to the resolution of HUS, whereas the reintroduction of gemcitabine treatment can result in recurrence; these findings support a causal association between gemcitabine and HUS. 5 In general, the cumulative gemcitabine doses reported in the literature are 20,000 mg/m 2 or 6 cycles, although descriptions have indicated that HUS cases can occur after a single dose.Patients are at greater risk for HUS when combined chemotherapeutic schemes are administered.In most cases, it is difficult to determine whether the presence of HUS is due to an underlying malignant condition or a patient's therapeutic regimen; however, poor disease control, evidence of unresolved or metastatic lesions, and clinical deterioration after chemotherapy is stopped provide evidence to support the possibility that an underlying neoplasia is triggering HUS. 5,11ultiple treatment strategies for gemcitabineassociated HUS have been proposed.6][7][8] .Nonetheless, there are cases in which patients exhibit no response; in these cases, overall mortality can reach 50%. 5 Steroids have been proposed for the treatment of these refractory cases, although steroid administration has produced controversial results.The major steroid treatment-related results described in the literature have involved the use of 1 mg/kg per day of prednisone for varying periods. 5,6,11A report has also described satisfactory responses to 200 mg/day of doxycycline, which may reflect its possible immunomodulatory role in gemcitabine-associated HUS. 5 Despite advancements in the understanding of TMAs, plasma exchanges remain the standard treatment for these conditions; in particular, plasma exchanges are immediately initiated upon a clinical suspicion of TMA, with variable success rates. 12owever, in cases of chemotherapy-associated HUS, the role of plasma exchanges is controversial, although this treatment remains the approach recommended by American Society for Apheresis guidelines. 13ertain reports have described adequate responses to this intervention; in particular, in a literature review of a total of 706 patients, Izzedine et al. observed that 85% of patients responded to plasma exchanges in combination with steroid treatment. 5However, other results, such as the findings described by Gore et al. 14 in a literature review of 44 cases from 2009, do not support the benefits of plasma exchanges.One confounding factor that prevents definitive conclusions from being obtained is that patients treated with plasma exchanges were more ill than patients who did not receive plasma exchanges.The number of plasma exchanges required to treat chemotherapy-associated HUS also has not been clearly defined; reports have described that up to 30 exchanges may be performed before positive responses are observed. 5everal literature reports have suggested that the administration of rituximab (monoclonal anti CD20antibody) is an alternative treatment in certain refractory cases of gemcitabine-associated TMA; it can produce favorable responses because this illness is associated with immune complexes as is suggested in our case by the decrease of serum complement levels. 14,15any uncertainties remain in cases of gemcitabine-associated TMA, and the incidence of gemcitabine-induced HUS likely continues to increase given the widespread use of this drug either alone or in combination with other chemotherapeutic agents.Therefore, medical professionals should be highly alert for gemcitabine-induced HUS because the early recognition and timely treatment of this syndrome could decrease morbidity and mortality.

Urinalysis
Literature sources recommend that for all patients receiving gemcitabine chemotherapy, basal hemolysis markers should be assessed before each cycle, and medical practitioners should be attentive to indications such as uncontrolled hypertension, pulmonary or peripheral edema, neurological deficits, and impaired renal function. 5,6,9,11n the case described in this report, we decided to use therapeutic approaches for gemcitabine-induced HUS that had been demonstrated to be beneficial in the literature.Therefore, in addition to stopping gemcitabine administration, the patient received dialysis and transfusion support, plasma therapy, steroid treatment, rituximab and doxycycline (as it was reported by Izzedine to have immunomodulatory properties). 5Clinical improvement was observed, but no conclusions can be drawn regarding which of these therapies was most effective in the described case.

Figure 1 .
Figure 1.Renal biopsy and histological findings -Collapsed glomeruli, capillary loop shrinkage, luminal obliteration, microthrombosis, glomerular congestion, and fragmented red blood cell were identified; these findings are consistent with thrombotic microangiopathy.Cellular debris and cylinders in the tubules were also observed, indicating the presence of associated acute tubular damage.

Figure 2 .
Figure 2. The evolution of lab tests during treatment -The evolution of laboratory parameters during the course of receiving the following treatments: 14 plasma exchange sessions (red arrows); hemodialysis from November 16, 2014 until December 31, 2014 (green arrows); and two doses of rituximab (black arrows).LDH values are presented using a 1x102 scale, and platelet values are presented using a 1x104 scale.