Letter to the Editor
Eculizumab as a treatment for atypical hemolytic uremic syndrome secondary to carfilzomib
Síndrome hemolítico urémico atípico secundario al uso de carfilzomib tratado con eculizumab
Candela Moliz
, Eduardo Gutiérrez, Teresa Cavero, Beatriz Redondo, Manuel Praga
Corresponding author
Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain
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It is one of the drugs used in the treatment of refractory multiple myeloma.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–4</span></a> The onset of atypical haemolytic uremic syndrome (aHUS) associated with the use of carfilzomib is a complication previously described in the literature.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5–10</span></a> We describe a case of aHUS secondary to carfilzomib effectively treated with eculizumab.</p><p id="par0010" class="elsevierStylePara elsevierViewall">This case involves a 71-year-old woman with refractory Bence-Jones Kappa multiple myeloma treated with carfilzomib, daratumumab and dexamethasone (KdD). The patient was admitted to the Haematology Department due to onset of malaise and fever 2 days after receiving the second cycle of KdD. Despite negative microbiology results, her blood pressure increased to over 180/100<span class="elsevierStyleHsp" style=""></span>mmHg on the fourth day. Blood tests found a decrease in haemoglobin of up to 6.8<span class="elsevierStyleHsp" style=""></span>g/dl and in platelets of up to 12,000, with an increase in LDH of up to 900<span class="elsevierStyleHsp" style=""></span>IU/l, accompanied by a deterioration of renal function, with serum creatinine levels of 2.6<span class="elsevierStyleHsp" style=""></span>mg/dl. Suspecting thrombotic microangiopathy (TMA), treatment with prednisone (1<span class="elsevierStyleHsp" style=""></span>mg/kg/day) and fresh plasma was started, with no improvement, and the patient was referred to the Nephrology Department for assessment.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Studies performed by the Nephrology Department showed 5–6% schistocytes per field on peripheral blood smear, no signs of malignant arterial hypertension on fundoscopy, undetectable haptoglobin in blood, and negative direct Coombs test. ADAMTS13 test was normal (ADAMTS13<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>50%). Other causes of aHUS and typical haemolytic uraemic syndrome (<span class="elsevierStyleItalic">STEC-HUS)</span> were ruled out, and genetic studies were not performed due to the high suspicion of a pharmacological cause. Carfilzomib was discontinued and treatment with eculizumab was started after administration of meningococcal prophylaxis with oral penicillin. Plasmapheresis was not performed due to the poor status of the patient and to avoid the comorbidity associated with the technique. One week after the third dose of eculizumab, serum creatinine levels had normalised (1.1<span class="elsevierStyleHsp" style=""></span>mg/dl) without the need for any haemodialysis sessions, and schistocytes had disappeared. From a haematological point of view, partial improvement was observed in haemoglobin and platelet levels, probably due to the underlying disease, although no schistocytes were found. The patient received 3 weekly doses of 900<span class="elsevierStyleHsp" style=""></span>mg of eculizumab, which was discontinued after improvement of renal function and stabilisation of haemolysis parameters.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Based on the accumulated evidence relating to the pathogenesis of this condition, we wonder whether treatment with eculizumab is justified. In the years since it was released, carfilzomib has been associated with several cases of TMA<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5–10</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The mechanism by which the damage occurs is thought to be related to the accumulated dose or to an alloimmune effect. Some authors suggest, however, that proteasome inhibitors decrease production of vascular endothelial growth factor (VEGF) by inhibiting the activity of proteins that regulate its genetic transcription. This results in endothelial and podocyte damage similar to that caused by anti-VEGF drugs.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,8</span></a> The latter is the most plausible of the 3 proposed mechanisms, since aHUS has occurred in patients who have only received 2 doses, as in our case, and not in other patients with higher cumulative doses. Likewise, the alloimmune mechanism is an unlikely culprit, given the context of administration of a plasma cell depleting drug in patients that are highly immunosuppressed due to previous chemotherapy and, as in our case, do not respond to immunosuppressive treatment (prednisone).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Secondary aHUS should be treated by withdrawing the causative agent.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2</span></a> In some series, plasmapheresis has been used, with no clear benefit for symptoms.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> In many cases, TMA is resolved by withdrawing the drug. However, as shown by the review published by Cavero et al., early use of eculizumab may be effective in cases of refractory TMA in which impaired renal function persists or worsens, or in life-threatening situations.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Recent studies have shown that the alternative pathway of the complement system is temporarily activated in cases of secondary aHUS. Based on this evidence, the new classification of thrombotic microangiopathies proposed in the KDIGO guidelines<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> now includes all secondary TMAs with ADAMTS13<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10% activity in the context of aHUS. Therefore, in cases of secondary aHUS that does not improve despite withdrawal of the causative agent, we recommend early, short-term administration of eculizumab.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Moliz C, Gutiérrez E, Cavero T, Redondo B, Praga M. Síndrome hemolítico urémico atípico secundario al uso de carfilzomib tratado con eculizumab. Nefrologia. 2019;39:86–88.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reference \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Number of cases \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical presentation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Drug used \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Measure taken \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Outcome \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chen et al.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HUS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carfilzomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of the drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Outcome<br>1 Haemodialysis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yui et al.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HUS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 Carfilzomib<br>3 Bortezomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of the drug<br>4 plasmapheresis<br>3 Eculizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 did not recover \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Qaqish et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HUS<br>TMA kidney biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carfilzomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of the drug<br>Plasmapheresis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Outcome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lodhi et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HUS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carfilzomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of the drug<br>Plasmapheresis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Outcome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sullivan et al.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HUS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carfilzomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of the drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Outcome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hobeika et al.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HTN and proteinuria<br>TMA kidney biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carfilzomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Withdrawal of the drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Outcome \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1978548.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Review of cases of TMA associated with the use of carfilzomib.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a «Kidney disease: Improving global outcomes» (KDIGO) controversies Conference" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.H. 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| Year/Month | Html | Total | |
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| 2024 November | 14 | 5 | 19 |
| 2024 October | 70 | 64 | 134 |
| 2024 September | 47 | 32 | 79 |
| 2024 August | 70 | 63 | 133 |
| 2024 July | 39 | 31 | 70 |
| 2024 June | 55 | 60 | 115 |
| 2024 May | 44 | 52 | 96 |
| 2024 April | 74 | 43 | 117 |
| 2024 March | 98 | 33 | 131 |
| 2024 February | 64 | 38 | 102 |
| 2024 January | 54 | 28 | 82 |
| 2023 December | 35 | 31 | 66 |
| 2023 November | 66 | 38 | 104 |
| 2023 October | 120 | 26 | 146 |
| 2023 September | 260 | 32 | 292 |
| 2023 August | 239 | 28 | 267 |
| 2023 July | 80 | 57 | 137 |
| 2023 June | 128 | 37 | 165 |
| 2023 May | 81 | 31 | 112 |
| 2023 April | 45 | 31 | 76 |
| 2023 March | 56 | 39 | 95 |
| 2023 February | 46 | 28 | 74 |
| 2023 January | 42 | 33 | 75 |
| 2022 December | 67 | 39 | 106 |
| 2022 November | 58 | 43 | 101 |
| 2022 October | 68 | 46 | 114 |
| 2022 September | 53 | 45 | 98 |
| 2022 August | 47 | 51 | 98 |
| 2022 July | 40 | 50 | 90 |
| 2022 June | 48 | 46 | 94 |
| 2022 May | 44 | 32 | 76 |
| 2022 April | 37 | 66 | 103 |
| 2022 March | 52 | 57 | 109 |
| 2022 February | 53 | 60 | 113 |
| 2022 January | 67 | 42 | 109 |
| 2021 December | 90 | 42 | 132 |
| 2021 November | 57 | 33 | 90 |
| 2021 October | 91 | 47 | 138 |
| 2021 September | 43 | 41 | 84 |
| 2021 August | 59 | 37 | 96 |
| 2021 July | 56 | 41 | 97 |
| 2021 June | 49 | 37 | 86 |
| 2021 May | 46 | 57 | 103 |
| 2021 April | 117 | 101 | 218 |
| 2021 March | 67 | 67 | 134 |
| 2021 February | 55 | 52 | 107 |
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| 2020 December | 51 | 21 | 72 |
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| 2020 September | 49 | 29 | 78 |
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| 2020 July | 41 | 23 | 64 |
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| 2020 May | 52 | 45 | 97 |
| 2020 April | 67 | 38 | 105 |
| 2020 March | 44 | 26 | 70 |
| 2020 February | 53 | 34 | 87 |
| 2020 January | 91 | 44 | 135 |
| 2019 December | 47 | 38 | 85 |
| 2019 November | 48 | 26 | 74 |
| 2019 October | 94 | 41 | 135 |
| 2019 September | 91 | 26 | 117 |
| 2019 August | 46 | 21 | 67 |
| 2019 July | 56 | 36 | 92 |
| 2019 June | 42 | 43 | 85 |
| 2019 May | 67 | 69 | 136 |
| 2019 April | 102 | 54 | 156 |
| 2019 March | 35 | 28 | 63 |
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