Letter to the Editor
Necrotizing glomerulonephritis in levamisole-contaminated cocaine use
Glomerulonefritis necrosante en el síndrome por consumo de cocaína y levamisol
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"cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Necrotizing glomerulonephritis in levamisole-contaminated cocaine use" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "76" "paginaFinal" => "78" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ana Esther Sirvent, Ricardo Enríquez, Encarnación Andrada, María Sánchez, Isabel Millán, César González" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Ana Esther" "apellidos" => "Sirvent" "email" => array:1 [ 0 => "nefro_elx@gva.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Ricardo" "apellidos" => "Enríquez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Encarnación" "apellidos" => "Andrada" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "María" "apellidos" => "Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Isabel" "apellidos" => "Millán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "César" "apellidos" => "González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital General Universitario de Elche, Elche, Alicante, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital General Universitario de Elche, Elche, Alicante, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Glomerulonefritis necrosante en el síndrome por consumo de cocaína y levamisol" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 703 "Ancho" => 975 "Tamanyo" => 241484 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Glomerulus with segmental fibrinoid necrosis and fibrous half-moon (SBP<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>40).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Spain is the country with the greatest incidence of cocaine use in adults,<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1,2</span></a> and consignments of levamisole-contaminated cocaine has increased in the last decade.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2,3</span></a> Regarding the use of cocaine/levamisole (C/L), a syndrome distinguished by the following has been reported: (1) purpuric, necrotic or ecchymotic skin lesions on the trunk, limbs and earlobes; the histological background is leukocytoclastic vasculitis or thrombotic vasculopathy; (2) leukopenia and neutropenia, and (3) positivity for different immune parameters<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2,3</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Kidney disease due to C/L is found to be scarcely documented.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">We describe the case of a patient who developed necrotizing glomerulonephritis, with kidney failure and nephrotic syndrome, associated with C/L use. To our knowledge, this would be the first publication with kidney biopsy in Spain.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient was a 47-year-old male referred for kidney failure and nephrotic syndrome evaluation. Two years earlier, he had had self-limited skin lesions on his right flank and his earlobes, and analyses confirmed neutropenia and positivity for ANAs and ANCAs (MPO and PR3). In the current admission he reported nocturia for the last few months, choluria, intermittent oedema and arthralgia in the left shoulder, elbow and knee. He denied the use of tobacco, toxins or any medicine. Physical examination: afebrile, with a blood pressure of 120/70<span class="elsevierStyleHsp" style=""></span>mmHg and all other parameters within normal limits. Laboratory test: haemoglobin 9.2<span class="elsevierStyleHsp" style=""></span>g/dl, leukocytes 3190<span class="elsevierStyleHsp" style=""></span>μl (neutrophils 54.6%), platelets 248,000<span class="elsevierStyleHsp" style=""></span>μl, prolonged APTT (41.7<span class="elsevierStyleHsp" style=""></span>min), Cr 2.66<span class="elsevierStyleHsp" style=""></span>mg/dl, albumin 2.9<span class="elsevierStyleHsp" style=""></span>g/dl, triglycerides 336<span class="elsevierStyleHsp" style=""></span>mg/dl, cholesterol 207<span class="elsevierStyleHsp" style=""></span>mg/dl, CK 167<span class="elsevierStyleHsp" style=""></span>U/l; rheumatoid factor, C3–C4, serum electrophoresis and thyroid hormones negative/normal. Antinuclear antibodies positive at 1/160, anti-DNA antibodies negative, lupus anticoagulant positive, IgG anticardiolipin antibodies negative, IgM 18.8<span class="elsevierStyleHsp" style=""></span>MPL/ml (positive<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>18<span class="elsevierStyleHsp" style=""></span>MPL/ml), cryoglobulins negative, c-ANCAs negative, p-ANCAs positive, MPO 17<span class="elsevierStyleHsp" style=""></span>IU/ml (positive<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10), PR3 35<span class="elsevierStyleHsp" style=""></span>IU/ml (positive<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>3). HLA-B27 negative. Serology for hepatitis B, hepatitis C and HIV viruses negative; previous exposure to cytomegalovirus, Epstein–Barr virus and parvovirus B19. Chest X-ray, echocardiogram and abdominal–pelvic CAT scan with no significant findings. Determination of toxins in urine was positive for cocaine. Sediment with 60–100 erythrocytes per field with 20%–30% dysmorphic, 6–12 leukocytes per field, culture negative, proteinuria 7680<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h with a non-selective glomerular pattern. The patient was questioned again and admitted to use of inhaled cocaine in the previous months. The kidney biopsy comprised 27 glomeruli: 3 with ischaemic changes, one with a fibrous crescent and the rest with segmental capillary tuft necrosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); immunofluorescence was not significant. Methylprednisolone (1.5<span class="elsevierStyleHsp" style=""></span>g IV), cyclophosphamide (750<span class="elsevierStyleHsp" style=""></span>mg IV) and oral prednisone 60<span class="elsevierStyleHsp" style=""></span>mg/day were administered in a decreasing regimen. After one month, serum creatinine level was 1.31<span class="elsevierStyleHsp" style=""></span>mg/dl.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The percentage of cocaine samples contaminated with levamisole was 80% in the United States in 2011,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a> and 48% in Spain between August and December 2009.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> It seems that cocaine is cut with levamisole because levamisole is a cheap powder with organoleptic characteristics similar to those of cocaine, and would increase cocaine's dopaminergic and sympathomimetic effects.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1,5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Levamisole is an anthelmintic agent that was used as an immunomodulator in humans until 2000. It promotes immune manifestations through various mechanisms: (1) it facilitates the actions of macrophages, B lymphocytes and T lymphocytes, and neutrophil chemotaxis; (2) it would alter immune tolerance and (3) it has direct toxicity on neutrophils and endothelial cells.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1,6</span></a> Cocaine in itself also may cause immune phenomena; therefore, it is possible for cocaine and levamisole to enhance each other. A jumbled or discordant immune pattern may be a key to diagnosis.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> ANCAs, ANAs, lupus anticoagulant and IgM anticardiolipin antibodies have been described; the presence of anti-DNA antibodies and hypocomplementaemia is rarer.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1,3,6,7</span></a> Regarding ANCAs, positivity for both MPO and PR3 may be seen. Discordance between the pattern by immunofluorescence and ELISA may also be seen,<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1,6</span></a> and indeed was observed in this case.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Levamisole is difficult to detect in urine due to its short half-life<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a>; however, demonstrated cocaine use plus characteristic clinical and laboratory abnormalities are sufficient to diagnose C/L syndrome.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">According to the series, both skin and/or joint manifestations (arthritis or arthralgia), which were present in our patient, are very common. Neutropenia is also common. A genetic susceptibility due to positivity for the HLA-B27 antigen has been shown in certain cases.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1,3</span></a> Neutropenia tends to improve upon suspending drug use.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a> Kidney manifestations due to C/L are asymptomatic urinary abnormalities, nephrotic syndrome and acute kidney failure.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">5,7,8</span></a> Although biopsied cases are few in number, pauci-immune extracapillary necrosing glomerulonephritis is the most common histological pattern,<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">6–9</span></a> and may or may not be accompanied by pulmonary haemorrhage.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> Abstention from C/L is the mainstay of treatment and, in addition, various immunosuppressants have been used.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">8,9</span></a> The patient's clinical course is not always good, and he or she may require maintenance dialysis.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">It would be appropriate to alert medical professionals to the onset of C/L use syndrome, above all in the presence of neutropenia and multiple autoimmune phenomena. Given that cocaine use is illegal and patients tend to deny it, it is important to maintain a high degree of clinical suspicion to reach a diagnosis.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Sirvent AE, Enríquez R, Andrada E, Sánchez M, Millán I, González C. Glomerulonefritis necrosante en el síndrome por consumo de cocaína y levamisol. Nefrologia. 2016;36:76–78.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 703 "Ancho" => 975 "Tamanyo" => 241484 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Glomerulus with segmental fibrinoid necrosis and fibrous half-moon (SBP<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>40).</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">ACLs: anticardiolipin antibodies; LA: lupus anticoagulant; PS: pathology study.</p>" "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Skin impairment</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Retiform purpura and skin necrosis (PS: leukocytoclastic vasculitis or thrombotic microangiopathy) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Typical location on earlobes and pinnae. Also on limbs, trunk and flanks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Musculoskeletal impairment: arthralgia</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleItalic">and/or arthritis</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>; <span class="elsevierStyleItalic">myalgia</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Leukopenia, neutropenia and/or agranulocytosis</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Serological abnormality: joint presence of multiple autoantibodies:</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Double positivity for ANCAs; discordance between pattern of immunofluorescence and antibodies by ELISA; atypical ANCAs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ACLs, LA, ANAs, anti-DNA antibodies, hypocomplementaemia \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1381854.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">According to the series, these may be the most common manifestations.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Clinical and serological characteristics of cocaine/levamisole use syndrome.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vasculopathy, hematological, and immune abnormalities associated with levamisole-contaminated cocaine use" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.A. 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