Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis
Eficacia y seguridad del tratamiento combinado con ciclosporina A y micofenolato de mofetilo en enfermos con glomeruloesclerosis segmentaria y focal ciclosporina-resistente
Read
11306
Timeswas read the article
2553
Total PDF
8753
Total HTML
Share statistics
array:21 [ "pii" => "X2013251411052001" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2011.Feb.10870" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2011;31:286-91" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5226 "formatos" => array:3 [ "EPUB" => 283 "HTML" => 4311 "PDF" => 632 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "X0211699511052004" "issn" => "02116995" "doi" => "10.3265/Nefrologia.pre2011.Feb.10870" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2011;31:286-91" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 9916 "formatos" => array:3 [ "EPUB" => 278 "HTML" => 8996 "PDF" => 642 ] ] "es" => array:12 [ "idiomaDefecto" => true "titulo" => "Eficacia y seguridad del tratamiento combinado con ciclosporina A y micofenolato de mofetilo en enfermos con glomeruloesclerosis segmentaria y focal ciclosporina-resistente" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "286" "paginaFinal" => "291" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10870_108_14458_es_10870_t1.jpg" "Alto" => 562 "Ancho" => 514 "Tamanyo" => 219045 ] ] "descripcion" => array:1 [ "es" => "Características clínicas, bioquímicas e histológicas basales" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Segarra Medrano, J. Vila Presas, L. Pou Clavé, J. Majó Masferrer, J. Camps Doménech" "autores" => array:5 [ 0 => array:2 [ "Iniciales" => "A." "apellidos" => "Segarra Medrano" ] 1 => array:2 [ "Iniciales" => "J." "apellidos" => "Vila Presas" ] 2 => array:2 [ "Iniciales" => "L." "apellidos" => "Pou Clavé" ] 3 => array:2 [ "Iniciales" => "J." "apellidos" => "Majó Masferrer" ] 4 => array:2 [ "Iniciales" => "J." "apellidos" => "Camps Doménech" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251411052001" "doi" => "10.3265/Nefrologia.pre2011.Feb.10870" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411052001?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511052004?idApp=UINPBA000064" "url" => "/02116995/0000003100000003/v0_201502091414/X0211699511052004/v0_201502091414/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "X2013251411051990" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2011.Apr.10812" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2011;31:292-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5461 "formatos" => array:3 [ "EPUB" => 306 "HTML" => 4428 "PDF" => 727 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Effects of Rapamycin on Angiomyolipomas in Patients with Tuberous Sclerosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "292" "paginaFinal" => "298" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectos de la rapamicina en los angiomiolipomas de pacientes con esclerosis tuberosa" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10812_108_17271_en_t1_10812.jpg" "Alto" => 231 "Ancho" => 600 "Tamanyo" => 110353 ] ] "descripcion" => array:1 [ "en" => "Evolution in size of angiomyolipomas" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Cristina Cabrera López, Teresa Martí, Violeta Catalá, Ferrán Torres, Silvia Mateu, Jose Ballarín Castán, Roser Torra Balcells" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Cristina" "apellidos" => "Cabrera López" ] 1 => array:2 [ "nombre" => "Teresa" "apellidos" => "Martí" ] 2 => array:2 [ "nombre" => "Violeta" "apellidos" => "Catalá" ] 3 => array:2 [ "nombre" => "Ferrán" "apellidos" => "Torres" ] 4 => array:2 [ "nombre" => "Silvia" "apellidos" => "Mateu" ] 5 => array:2 [ "nombre" => "Jose" "apellidos" => "Ballarín Castán" ] 6 => array:2 [ "nombre" => "Roser" "apellidos" => "Torra Balcells" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699511051993" "doi" => "10.3265/Nefrologia.pre2011.Apr.10812" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511051993?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411051990?idApp=UINPBA000064" "url" => "/20132514/0000003100000003/v0_201502091638/X2013251411051990/v0_201502091638/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "X201325141105201X" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2011.Feb.10820" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2011;31:275-85" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6875 "formatos" => array:3 [ "EPUB" => 295 "HTML" => 4441 "PDF" => 2139 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Ethical challenges in transplant practice in Latin America: the Aguascalientes Document" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "275" "paginaFinal" => "285" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Desafíos éticos en la práctica de trasplantes en América Latina: Documento de Aguascalientes" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => " Documento de Aguascalientes, A. Baquero, J. Alberú" "autores" => array:3 [ 0 => array:1 [ "apellidos" => "Documento de Aguascalientes" ] 1 => array:2 [ "Iniciales" => "A." "apellidos" => "Baquero" ] 2 => array:2 [ "Iniciales" => "J." "apellidos" => "Alberú" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699511052012" "doi" => "10.3265/Nefrologia.pre2011.Feb.10820" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511052012?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X201325141105201X?idApp=UINPBA000064" "url" => "/20132514/0000003100000003/v0_201502091638/X201325141105201X/v0_201502091638/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "286" "paginaFinal" => "291" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "A. Segarra Medrano, J. Vila Presas, L. Pou Clavé, J. Majó Masferrer, J. Camps Doménech" "autores" => array:5 [ 0 => array:4 [ "Iniciales" => "A." "apellidos" => "Segarra Medrano" "email" => array:1 [ 0 => "alsegarr@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:3 [ "Iniciales" => "J." "apellidos" => "Vila Presas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 2 => array:3 [ "Iniciales" => "L." "apellidos" => "Pou Clavé" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 3 => array:3 [ "Iniciales" => "J." "apellidos" => "Majó Masferrer" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 4 => array:3 [ "Iniciales" => "J." "apellidos" => "Camps Doménech" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Vall d'Hebron, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Servicio de Bioquímica, Hospital Vall d'Hebron, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Vall d'Hebron, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eficacia y seguridad del tratamiento combinado con ciclosporina A y micofenolato de mofetilo en enfermos con glomeruloesclerosis segmentaria y focal ciclosporina-resistente" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10870_108_16074_en_t1_10870_t1.jpg" "Alto" => 650 "Ancho" => 600 "Tamanyo" => 183374 ] ] "descripcion" => array:1 [ "en" => "Baseline clinical, biochemical and histological characteristics" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Current available evidence shows that for patients with focal segmental glomerulosclerosis (FSGS) who have steroid-resistant nephrotic syndrome, treatment with cyclosporine A (CsA) can improve the long-term prognosis for renal function. However, despite initial reports that up to 75% of patients may have full or partial remission of proteinuria, more than 50% of steroid-resistant cases also develop resistance to treatment with cyclosporine and, in the long term, suffer progressive kidney disease. For these cases, apart from hypertension control and angiotensin II blockers, there is no treatment with proven efficacy that would modify the clinical course of the disease.<span class="elsevierStyleSup">1-4</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In recent years, there have been various observational studies analysing the efficacy and safety of mycophenolate mofetil (MMF), in monotherapy and in combination with steroids, in the treatment of idiopathic FSGS, with conflicting response rates that are generally low.<span class="elsevierStyleSup">5-13</span> Studies carried out in organ transplantation show that the combination of MMF and CsA has an additive or synergistic immunosuppressive effect.<span class="elsevierStyleSup">14,15</span> This effect could be useful in treating patients with FSGS who show resistance to steroids and/or CsA. However, the efficacy of this combination in FSGS has only been described in a single observational study in steroid-resistant patients who also received other immunosuppressants.<span class="elsevierStyleSup">16</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The aim of this pilot study was to analyse the potential efficacy and safety of CsA and MMF therapy in a group of patients with primary CsA-resistant FSGS.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">PATIENTS AND METHODS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Design</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Observational study with prospective follow-up.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Between 1996 and 2004, 27 patients who met the following criteria were included in the study: </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">1. Histological diagnosis of FSGS (all biopsies were analysed by the same pathologists).</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">2. Exclusion of secondary aetiologies including: renal mass reduction, morbid obesity, HIV-related nephropathy, heroin or cocaine use, analgesic treatment, vesicoureteral reflux and obstructive sleep apnoea.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">3. Previous resistance to a treatment cycle of six months with steroids and a treatment cycle of six months with CsA, defined as persistent proteinuria >3.5g/day.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">4. Glomerular filtration rate >60ml/min/1.73m<span class="elsevierStyleSup">2</span>.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">5. No other therapy with immunosuppressive or non-steroidal anti-inflammatory drugs in the six months prior to inclusion.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">6. No family history of chronic kidney disease or renal replacement therapy.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">7. Absence of contraindications for treatment with MMF.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">8. Provided written informed consent.<span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Studies prior to inclusion</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">After verifying resistance to steroids and CsA, all patients were followed for at least six months before being included in the study. During this period, they were only prescribed a low-sodium diet (5g/day) and treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). The dosage of these drugs was adjusted to achieve blood pressure readings under 140/80. If necessary, amlodipine and/or furosemide treatment was included. None of the patients were treated with combined ACEi/ARB or with aldosterone antagonists. In case of hypercholesterolaemia, statins were prescribed to achieve LDL cholesterol levels under 120 mg/dl.  </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Treatment protocol</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">After inclusion in the study and throughout the follow-up, ACEi and ARB doses were kept constant. All patients received treatment with CsA at an initial dose of 4mg/kg/day, which was later adjusted to maintain trough levels between 150 and 200ng/ml (12h post-dose in total blood). The MMF dose was 2000mg/day in all cases. </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">After 12 months of treatment, patients with persistent proteinuria >3.5g/day were considered resistant. The study proceeded with the withdrawal of both drugs. If there was evidence of full or partial remission of proteinuria, the treatment could be continued for another 12 months. At the end of this period, the dose was reduced by 25% each month until full withdrawal had been achieved.<span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Anatomopathological</span><span class="elsevierStyleBold">analysis of renal biopsies</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">All biopsies were stained with haematoxylin-eosin, PAS and Masson's trichrome for morphological analysis. Immunofluorescence studies were performed with antibodies against IgA, IgG, IgM, C3, fibrinogen and light chains. In each biopsy, the percentage of glomeruli with total or segmental sclerosis was calculated. The extent of interstitial fibrosis was measured using quantitative morphometry, in 5µm sections stained with Masson's trichrome, using an Olympus WCUE-2 autoanalyser.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Operational definitions</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">Proteinuria was considered to be in the nephrotic range for readings >3.5g/day. Nephrotic syndrome was defined as proteinuria >3.5g/day combined with hypoalbuminaemia <3.5g/dl. Complete remission: proteinuria <0.3g/day in two consecutive tests. Partial remission: proteinuria <3.5g/day and >0.3g/day. Arterial hypertension: Systolic blood pressure (SBP) >140mm Hg or diastolic blood pressure (DBP) >90mm Hg. Chronic renal failure: GFR<60ml/min calculated by endogenous creatinine clearance. Chronic renal failure (Stage 5): GFR<15ml/min. Acute cyclosporine renal toxicity: >30% increase in serum creatinine reversible after 25% reduction in CsA dose.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Clinical follow-up and monitoring</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">After inclusion in the study, patients were monitored on an outpatient basis each month for the first six months, every two months until the end of the first year and every four months during the remaining follow-up period until 60 months had been completed or renal replacement therapy was initiated. At each follow-up visit, SBP and DBP were measured. A general biochemical examination was performed that included serum creatinine, liver function, electrolytes, endogenous creatinine clearance, glycaemia, CsA level and 24-hour proteinuria. Glomerular filtration was calculated using endogenous creatinine clearance. Urinary protein excretion was quantified in 24-hour urine samples.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">If there was evidence of a greater than 30% increase in creatinine, the CsA dose was reduced by 25% and another renal function check was performed seven days later. For those cases where gastrointestinal symptoms appeared after initiating MMF therapy, the total dose was reduced by 50% for one week. The dose was subsequently increased progressively until the maximum tolerated dose was reached. MMF therapy was suspended for cases of persistent gastrointestinal symptoms, onset of leukopaenia or fever.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Outcome variables</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The primary outcome variable was the number of patients with total or partial remission of proteinuria after 12 months of treatment. The secondary variables were the number of patients with proteinuria reduced to non-nephrotic levels, the presence of progressive kidney disease or the need for renal replacement therapy during follow-up and the identification of independent predictors of the evolution of the glomerular filtration slope.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistical analysis</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The results are expressed as the mean±1 SD. Changes in urinary protein excretion and GFR throughout treatment were analysed using an analysis of variance for repeated measures after a logarithmic transformation of both variables. The GFR slope was used as a criterion for loss of renal function. It was estimated by including at least 10 GFR measurements, and a linear progression model was assumed. A simple linear regression analysis was performed using the logarithm of the glomerular filtration slope up to the end of follow-up or the start of the renal replacement therapy as the dependent variable. To analyse independent predictors of the glomerular filtration evolution, with the variables that had a significant association in the univariate analysis, a stepwise multiple regression model was created. All values with <span class="elsevierStyleItalic">P</span><.05 were considered significant.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The study met the provisions set forth in the Declaration of Helsinki and was approved by the hospital ethics committee. The treatment was authorised by the Spanish ministry of health with the provision for compassionate use in all patients.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Baseline characteristics  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">Clinical and biochemical variables</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Table 1 shows the main characteristics of the sample of 27 patients studied.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">Anatomopathological data</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">According to the morphological pattern, all patients had predominantly peripheral FSGS lesions (classic form, NOS). None of the patients had collapsing glomerulonephritis. Immunofluorescence showed focal IgM deposits in 16 patients, C3 in four cases, IgM and C3 in four, and a lack of deposits in three patients. A significant correlation was observed between GFR and the number of glomeruli with total sclerosis (r=0.48; <span class="elsevierStyleItalic">P</span><.01) and the extent of interstitial fibrotic lesions (r=0.52; <span class="elsevierStyleItalic">P</span><.01).  </p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Response to treatment </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">After the treatment period was over, none of the patients had full remission. There were no significant changes in proteinuria in 23 patients. Four patients (14.8%) had a decrease in proteinuria to below 3.5g/day (partial remission). These four patients had baseline proteinuria (5.62±2.19 versus 8.1±2.96g/day; <span class="elsevierStyleItalic">P</span>=.042) and significantly lower GFR slopes prior to inclusion in the study (–0.08±0.12 versus –0.69±0.38; <span class="elsevierStyleItalic">P</span>=.003) and greater baseline renal function (99.6±12.9 versus 85.05±15.5ml/min/1.73 m<span class="elsevierStyleSup">2</span>; <span class="elsevierStyleItalic">P</span>=.003) than patients without changes in urinary protein excretion. Treatment with CsA and MMF in these four patients was maintained for an average of 17.6 months (maximum: 24 months, minimum: 17 months). After drug withdrawal, proteinuria was keep at levels lower than 3.5g/day in three patients throughout the follow-up. In the fourth patient, it increased to levels of 5.5g/day, but a new pattern of immunosuppressive treatment was not indicated.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">During the five years of follow-up, patient GFR suffered a significant decline (mean absolute decline: –32.5±13.77ml/min/1.73 m<span class="elsevierStyleSup">2</span>;<span class="elsevierStyleSup"> </span><span class="elsevierStyleItalic">P</span>=.0001; average slope: –0.54±0.19ml/min/month; <span class="elsevierStyleItalic">P</span>=.001). Sixteen out of the 27 patients (59.2%) met the criteria for progressive renal failure or stage 5 CKD at the end of follow-up. Regarding patients with no evidence of significant loss of renal function, these 16 patients had significantly lower baseline levels of GFR (70.3±7.39 versus 97±10.3ml/min/1.73 m<span class="elsevierStyleSup">2;</span><span class="elsevierStyleItalic">P</span>=.001), greater baseline proteinuria (10.56±3.2 versus 6.1±2.42g/day; <span class="elsevierStyleItalic">P</span>=.006), evidence of a faster drop in renal function during the follow-up prior to inclusion in the study (–1.3±0.8 versus –0.19±0.41ml/min/month; <span class="elsevierStyleItalic">P</span>=.002) and greater proteinuria during the follow-up after treatment with CsA and MMF (7.2±3.1 versus 4.1±1.93g/day; <span class="elsevierStyleItalic">P</span>=.033). The slope of glomerular filtration loss in the four patients with partial remission was significantly lower than in the patients who did not respond (–0.073±0.19 versus –0.71±0.29; <span class="elsevierStyleItalic">P</span>=.002). However, none of the four patients showed a significant difference between the slopes prior to and after the treatment period. In the entire sample, there were no significant differences between the slope of GFR loss prior to inclusion and that observed during the five years of follow-up after treatment with CsA and MMF (–0.63±0.9ml/min/month versus –0.54±0.19ml/min/month; <span class="elsevierStyleItalic">P</span>=NS). The only variables associated with the glomerular filtration slope throughout the follow-up period in the multivariate analysis were initial glomerular filtration (<span class="elsevierStyleItalic">P</span>=.041) and mean proteinuria during the follow-up (<span class="elsevierStyleItalic">P</span>=.037).</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Side effects  </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">All patients completed the 12-month treatment period. Gastrointestinal side effects appeared in 33.3% of the patients. In all cases, the symptoms were mild and disappeared when the MMF dose was reduced. In none of the cases was it necessary to withdraw treatment. Transient acute renal toxicity was observed in 14.8% of the patients. Three patients (11.1%) had gingival hyperplasia. Some 22.2% of the patients required an increase in the dose and/or number of anti-hypertensive drugs during the 12 months of treatment with CsA and MMF (Table 3 shows the anti-hypertensive treatment used throughout the follow-up period). None of the patients had episodes of fever or leukopaenia.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara">This study was established with the aim of analysing the potential efficacy and safety of the CsA and MMF treatment in patients with steroid- and CsA-resistant FSGS. When it was designed, the clinical usefulness of CsA in the treatment of FSGS had been adequately shown in randomised clinical trials,<span class="elsevierStyleSup">1-3</span> but there was no data on the potential efficacy of MMF. The decision to combine both drugs was based exclusively on the possible additive immunosuppressive effect described in organ transplantation.<span class="elsevierStyleSup">14,15</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The observed results indicate that for patients with resistance to glucocorticoids and CsA, treatment with CsA and MMF for 12 months does not induce total remission of proteinuria. Throughout the follow-up period, however, a moderate but significant reduction in proteinuria was observed in four patients. Considering the relationship observed between mean proteinuria and the glomerular filtration slope during the follow-up, treatment with CsA and MMF would be expected to have a beneficial effect in the preservation of renal function in patients who had a greater reduction in proteinuria. However, none of the four cases showed significant differences between the pre- and post-treatment slopes of glomerular filtration loss. The improved evolution of this small subgroup of patients is associated with the course of the disease prior to inclusion in the study, but not with the effect of the treatment. A reasonable explanation for this would be that since patients with greater reductions in baseline proteinuria also showed significantly lower levels of proteinuria, better renal function and lower slope of glomerular filtration loss, they may have suffered from a histologically indistinguishable form of FSGS with slower more benign evolution. Both the percentage and the type of response observed in our patients was lower than those reported in the only study published to date that examines the effect of combining MMF with calcineurin inhibitors in patients with FSGS.<span class="elsevierStyleSup">16</span> This is probably because that study included patients with resistance to glucocorticoids, while our study included patients with resistance to glucocorticoids and CsA. Moreover, the data observed in our cohort of patients in terms of proteinuria reduction are at the lower limit of the interval described in observational studies that analyse the potential efficacy of MMF in FSGS adults (in monotherapy or combined with steroids).<span class="elsevierStyleSup">5-13</span> Overall, the available information does not suggest that the combination of CsA and MMF has a relevant role in inducing remission in patients with multiple resistance.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Although this is not a controlled study, the likelihood of progression to chronic renal failure and renal replacement therapy observed in the whole sample of patients after five years of follow-up does not differ from that described in most series of symptomatically treated patients with resistance to CsA.<span class="elsevierStyleSup">3,4,17-19</span> This would also be an argument against a possible beneficial effect of the combination of CsA and MMF for long-term preservation of renal function.  </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">All patients included had proteinuria in the nephrotic range and hypoalbuminaemia and were carefully studied to rule out secondary aetiologies. However, we are not able to definitively reject that some of them present with forms of FSGS that can not be modified using immunosuppressive treatment. In this regard, it should be noted that a genetic study was not performed in any of the cases, and therefore it is possible that some of the patients who were classified as having idiopathic forms actually suffered sporadic mutations of the podocyte proteins. This limitation is common to all studies performed to date that analyse the effectiveness of various immunosuppressants in FSGS patients. However, given the low reported prevalence of these types of mutations in FSGS adults with no family history of the disease, it is unlikely that this is the main reason for the observed lack of response to immunosuppressive treatment.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The treatment was well tolerated but was not without side effects. The most significant was the high incidence of gastrointestinal symptoms, which were mild and did not require withdrawal of either of the two drugs.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In conclusion, the data from this pilot study show that for CsA-resistant FSGS patients, treatment combination of CsA and MMF for 12 months does not significantly modify the evolution of renal function, although it may induce partial reductions in proteinuria in some patients.</p><p class="elsevierStylePara"><a href="grande/10870_108_16074_en_t1_10870_t1.jpg" class="elsevierStyleCrossRefs"><img src="10870_108_16074_en_t1_10870_t1.jpg" alt="Baseline clinical, biochemical and histological characteristics"></img></a></p><p class="elsevierStylePara">Table 1. Baseline clinical, biochemical and histological characteristics</p><p class="elsevierStylePara"><a href="grande/10870_108_16075_en_t2_10870.jpg" class="elsevierStyleCrossRefs"><img src="10870_108_16075_en_t2_10870.jpg" alt="Evolution of proteinuria and renal function throughout follow-up "></img></a></p><p class="elsevierStylePara">Table 2. Evolution of proteinuria and renal function throughout follow-up </p>" "pdfFichero" => "P1-E521-S2948-A10870-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441075" "palabras" => array:1 [ 0 => "Resistencia a ciclosporina" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441077" "palabras" => array:1 [ 0 => "Glomeruloesclerosis focal y segmentaria" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441079" "palabras" => array:1 [ 0 => "Micofenolato de mofetil" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441081" "palabras" => array:1 [ 0 => "Ciclosporina" ] ] ] "en" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441076" "palabras" => array:1 [ 0 => "Cyclosporine resistance" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441078" "palabras" => array:1 [ 0 => "Focal and segmental glomeruloesclerosis" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441080" "palabras" => array:1 [ 0 => "Mycophenolate mofetil" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441082" "palabras" => array:1 [ 0 => "Cyclosporin A" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction:</span> The combination of cyclosporin A (CsA) and mycophenolate mofetil (MMF) has a synergistic immunosuppressive effect and, as a result, it may induce remission of nephrotic syndrome in patients with steroid- and CsA-resistant focal segmental glomerulosclerosis (FSGS). <span class="elsevierStyleBold">Objective:</span> To analyse the efficacy and safety of the combined CsA and MMF treatment in patients with cyclosporin A-resistant FSGS. <span class="elsevierStyleBold">Patients and methods:</span> Twenty-seven patients with CsA-resistant FSGS were treated for 12 months with CsA (4mg/kg/day) combined with MMF (2g/day). The overall follow-up was 5 years. The proportion of patients with remission of proteinuria and the evolution of kidney function after 5 years were used to measure the outcome. <span class="elsevierStyleBold">Results:</span> At the end of the treatment period, no patients were in complete remission and 4 patients (14.8%) had reduced proteinuria to values <3.5g/day. These patients had significantly lower baseline proteinuria (5.62±2.19 compared to 8.1±2.96g/day, <span class="elsevierStyleItalic">P</span>=.042), significantly lower GFR (-0.08 compared to -0.69±0.38; <span class="elsevierStyleItalic">P</span>=.003) and higher baseline kidney function (99.6±12.9 compared to 85.05±15.5ml/min; <span class="elsevierStyleItalic">P</span>=.003). Sixteen out of the 27 patients (59.2%) had progressive or stage 5 kidney disease at the end of the follow-up period. Adverse gastrointestinal effects were observed in 33.3% of the patients and acute transitory nephrotoxicity in 14.8%. The dosage and/or number of anti-hypertensive drugs had to be increased in 22.2% of patients during the 12 months of treatment. <span class="elsevierStyleBold">Conclusions:</span> Twelve months of combined CsA and MMF therapy does not significantly alter the evolution of kidney function in patients with cyclosporin-resistant FSGS, although it may induce partial reductions in proteinuria.</p>" ] "es" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducción:</span> La asociación de ciclosporina A (CsA) y micofenolato mofetil (MMF) tiene un efecto inmunosupresor sinérgico y, en consecuencia, podría  inducir una remisión del síndrome nefrótico en enfermos con glomeruloesclerosis segmentaria y focal resistente a esteroides y a CsA. <span class="elsevierStyleBold">Objetivo:</span> Analizar la eficacia y el perfil de seguridad de la asociación CsA y MMF en enfermos con GSF resistente a ciclosporina A. <span class="elsevierStyleBold">Pacientes y método:</span> 27 enfermos con GSF resistente a CsA recibieron tratamiento con CsA (4 mg/kg/día) asociada a MMF (2 g/día) durante 12 meses. El seguimiento total fue de 5 años. Como medida de resultado, se consideró la proporción de enfermos con remisión de la proteinuria y la evolución de la función renal a los 5 años. <span class="elsevierStyleBold">Resultados:</span> Al finalizar el período de tratamiento, ningún paciente presentó remisión completa; 4 pacientes (14,8%) presentaron reducción de proteinuria a valores <3,5 g/día. Estos enfermos presentaban proteinuria basal (5,62 ± 2,19 frente a 8,1 ± 2,96 g/día, p = 0,042) y pendientes de FG  (–0,08 ± 0,12 frente a –0,69 ± 0,38; p = 0,003) significativamente inferiores y mayor función renal basal (99,6 ± 12,9 frente a 85,05 ± 15,5 ml/min; p = 0,003). Dieciséis de los 27 enfermos (59,2%) presentaron una enfermedad renal progresiva o estadio V al final del período de seguimiento. Se apreciaron efectos adversos gastrointestinales en el 33,3% de los enfermos y nefrotoxicidad aguda transitoria en el 14,8%. El 22,2% de los enfermos precisó un incremento en la dosis y/o número de hipotensores durante los 12 meses de tratamiento. <span class="elsevierStyleBold">Conclusiones:</span> En enfermos con GSF resistente a ciclosporina, el tratamiento con asociación de CsA y MMF durante 12 meses, aunque puede inducir reducciones parciales de la proteinuria, no modifica significativamente el curso evolutivo de la función renal.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10870_108_16074_en_t1_10870_t1.jpg" "Alto" => 650 "Ancho" => 600 "Tamanyo" => 183374 ] ] "descripcion" => array:1 [ "en" => "Baseline clinical, biochemical and histological characteristics" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10870_108_16075_en_t2_10870.jpg" "Alto" => 753 "Ancho" => 600 "Tamanyo" => 189624 ] ] "descripcion" => array:1 [ "en" => "Evolution of proteinuria and renal function throughout follow-up" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ponticelli C, Rizzoni G, Edefonti A, Altieri P, et al. A randomized trial of cyclosporine\u{A0} in steroid-resistant idiopathic nephrotic syndrome. Kidney Int 1993;43:1377-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8315953" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0735109712028136" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lee HY, Kim HS, Kang CM, Kim SG, Kim MJ. The efficacy of cyclosporine A in adult nephrotic syndrome with minimal change disease and focal-segmental glomerulosclerosis: A multicenter study in Korea. Clin Nephrol 1995;43:375-81. <a href="http://www.ncbi.nlm.nih.gov/pubmed/7554521" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Meyrier A, Noel LH, Auriche P, Callard P, and the Collaborative Group of the Société de Néphrologie. Long-term term renal tolerance of cyclosporine A treatment in adult idiopathic nephrotic syndrome. Kidney Int 1994;45:1446-56. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8072258" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Cattran DC, Appel GB, Herbert LA, Hunsicker LG, et al, for the North America Nephrotic Syndrome Study Group. A randomized trial of cyclosporine in patients with steroid-resistant focal glomerulosclerosis. Kidney Int 1999;56:2220-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10594798" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Briggs WA, Choi MJ, Scheel PJ. Follow-up on mycophenolate treatment of glomerular disease. Am J Kidney Dis 1998;31:898-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9590208" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0735109709012984" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Radhakrishnan J, Wang MM, Matalon A, Cattran DC, Appel GB. Mycophenolate mofetil treatment of idiopathic focal segmental glomerulosclerosis [Abstract]. J Am Soc Nephrol 1999;114A:A584. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20431041" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0735109711031445" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Segarra A, Amoedo ML, Martínez García JM, Pons S, Praga M, et al. Efficacy and safety of «rescue therapy» with mycophenolate mofetil in resistant primary glomerulonephritis-a multicenter study. Nephrol Dial Transplant 2007;22(5):1351-60. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17311833" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Choi, MJ, Eustace, JA, Gimenez LF, Atta MG, Scheel PJ, Sothinathan R, et al.\u{A0}Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 2002;61:1098-114. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11849465" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Day CJ, Cockwell P, Lipkin GW, Savage CO, Howie AJ, Adu D. Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome. Nephrol Dial Transplant 2002;17:2011-3. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12401863" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Levin ML. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 2002;62:1475. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12234326" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Bullo B, Zdrojewski Z, Rutkowski B. Mycophenolate mofetil (MMF) therapeutic approach in patients with chronic glomerulonephritis (GN). Kidney Int 2003;64:1139. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12911572" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Dimitrakov DJ, Nikolov DG, Dimitrakov JD, Despotov TB, et al. Effect of mycophenolate mofetil (Cell Cept) in the treatment of immune glomerulopathies. Folia Med (Plovdiv) 2004;46:15-8." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Cattran DC, Wang MM, Appel G, Matalon A, Briggs W. Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis. Clin Nephrol 2004;62(6):405-11. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15630898" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ostraat O, Qi Z, Olausson M, Gannedahl G, Tufveson G, Ekberg H. Additive immunosuppressive effect of combined mycophenolate mofetil and cyclosporine A in experimental rat cardiac transplantation. Transplant Proc 1995;27(6):3540. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8540091" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0140673610606745" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ostraat O, Qi Z, Olausson M, Tufveson G, Ekberg H. Mycophenolate mofetil, azathioprine and cyclophosphamide enhanced efficacy combined with cyclosporine in rat cardiac transplantation. Scand J Immunol 1997;45(4):343-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9105419" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "El-Reshaid K, El-Reshaid W, Madda J. Combination of immunosuppressive agents in treatment of steroid-resistant minimal change disease and primary focal segmental glomerulosclerosis.\u{A0}Ren Fail 2005;27(5):523-30. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16152989" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 1995;25(4):534-42. <a href="http://www.ncbi.nlm.nih.gov/pubmed/7702047" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Ponticelli C, Villa M, Banfi G, et al. Can prolonged treatment improve the prognosis in adults with focal segmental glomerulosclerosis? Am J Kidney Dis 1999;34:618-25.\u{A0}\u{A0} <a href="http://www.ncbi.nlm.nih.gov/pubmed/10516340" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Chun MJ, Korbet SM, Schwartz MM,\u{A0}Lewis EJ. Focal Segmental Glomerulosclerosis in Nephrotic Adults: Presentation, Prognosis, and Response to Therapy of the Histological Variants. J Am Soc Nephrol 2004;15:2169-77. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15284302" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Troyanov S, Wall CA, Miller JA, et al. Focal and segmental glomerulosclerosis: Definition and relevance of a partial remission. J Am Soc Nephrol 2005;16(4):1061-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15716334" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003100000003/v0_201502091638/X2013251411052001/v0_201502091638/en/main.assets" "Apartado" => array:4 [ "identificador" => "35441" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Originals" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003100000003/v0_201502091638/X2013251411052001/v0_201502091638/en/P1-E521-S2948-A10870-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411052001?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 23 | 6 | 29 |
| 2024 October | 85 | 30 | 115 |
| 2024 September | 124 | 41 | 165 |
| 2024 August | 121 | 90 | 211 |
| 2024 July | 117 | 55 | 172 |
| 2024 June | 113 | 56 | 169 |
| 2024 May | 127 | 39 | 166 |
| 2024 April | 82 | 41 | 123 |
| 2024 March | 117 | 31 | 148 |
| 2024 February | 78 | 32 | 110 |
| 2024 January | 81 | 26 | 107 |
| 2023 December | 77 | 44 | 121 |
| 2023 November | 77 | 38 | 115 |
| 2023 October | 110 | 37 | 147 |
| 2023 September | 94 | 33 | 127 |
| 2023 August | 104 | 28 | 132 |
| 2023 July | 113 | 42 | 155 |
| 2023 June | 84 | 22 | 106 |
| 2023 May | 84 | 32 | 116 |
| 2023 April | 81 | 11 | 92 |
| 2023 March | 80 | 20 | 100 |
| 2023 February | 42 | 27 | 69 |
| 2023 January | 75 | 27 | 102 |
| 2022 December | 35 | 29 | 64 |
| 2022 November | 88 | 38 | 126 |
| 2022 October | 65 | 67 | 132 |
| 2022 September | 45 | 22 | 67 |
| 2022 August | 103 | 42 | 145 |
| 2022 July | 108 | 46 | 154 |
| 2022 June | 49 | 41 | 90 |
| 2022 May | 59 | 36 | 95 |
| 2022 April | 55 | 63 | 118 |
| 2022 March | 70 | 75 | 145 |
| 2022 February | 66 | 39 | 105 |
| 2022 January | 113 | 33 | 146 |
| 2021 December | 84 | 46 | 130 |
| 2021 November | 62 | 35 | 97 |
| 2021 October | 75 | 47 | 122 |
| 2021 September | 46 | 28 | 74 |
| 2021 August | 64 | 37 | 101 |
| 2021 July | 78 | 35 | 113 |
| 2021 June | 46 | 17 | 63 |
| 2021 May | 78 | 40 | 118 |
| 2021 April | 144 | 71 | 215 |
| 2021 March | 99 | 34 | 133 |
| 2021 February | 86 | 20 | 106 |
| 2021 January | 64 | 14 | 78 |
| 2020 December | 56 | 11 | 67 |
| 2020 November | 52 | 24 | 76 |
| 2020 October | 32 | 23 | 55 |
| 2020 September | 50 | 12 | 62 |
| 2020 August | 53 | 7 | 60 |
| 2020 July | 54 | 9 | 63 |
| 2020 June | 75 | 14 | 89 |
| 2020 May | 66 | 18 | 84 |
| 2020 April | 46 | 21 | 67 |
| 2020 March | 61 | 9 | 70 |
| 2020 February | 65 | 19 | 84 |
| 2020 January | 68 | 33 | 101 |
| 2019 December | 66 | 21 | 87 |
| 2019 November | 58 | 24 | 82 |
| 2019 October | 60 | 11 | 71 |
| 2019 September | 67 | 15 | 82 |
| 2019 August | 70 | 11 | 81 |
| 2019 July | 64 | 29 | 93 |
| 2019 June | 57 | 16 | 73 |
| 2019 May | 71 | 15 | 86 |
| 2019 April | 96 | 35 | 131 |
| 2019 March | 68 | 24 | 92 |
| 2019 February | 29 | 11 | 40 |
| 2019 January | 44 | 17 | 61 |
| 2018 December | 114 | 36 | 150 |
| 2018 November | 107 | 20 | 127 |
| 2018 October | 102 | 12 | 114 |
| 2018 September | 79 | 20 | 99 |
| 2018 August | 45 | 16 | 61 |
| 2018 July | 47 | 23 | 70 |
| 2018 June | 40 | 12 | 52 |
| 2018 May | 51 | 16 | 67 |
| 2018 April | 35 | 3 | 38 |
| 2018 March | 45 | 6 | 51 |
| 2018 February | 45 | 7 | 52 |
| 2018 January | 34 | 5 | 39 |
| 2017 December | 63 | 11 | 74 |
| 2017 November | 36 | 4 | 40 |
| 2017 October | 52 | 9 | 61 |
| 2017 September | 44 | 13 | 57 |
| 2017 August | 50 | 8 | 58 |
| 2017 July | 52 | 15 | 67 |
| 2017 June | 57 | 16 | 73 |
| 2017 May | 78 | 12 | 90 |
| 2017 April | 72 | 11 | 83 |
| 2017 March | 60 | 6 | 66 |
| 2017 February | 37 | 12 | 49 |
| 2017 January | 49 | 11 | 60 |
| 2016 December | 67 | 6 | 73 |
| 2016 November | 62 | 10 | 72 |
| 2016 October | 103 | 10 | 113 |
| 2016 September | 120 | 5 | 125 |
| 2016 August | 230 | 11 | 241 |
| 2016 July | 181 | 15 | 196 |
| 2016 June | 130 | 0 | 130 |
| 2016 May | 136 | 0 | 136 |
| 2016 April | 102 | 0 | 102 |
| 2016 March | 123 | 0 | 123 |
| 2016 February | 106 | 0 | 106 |
| 2016 January | 119 | 0 | 119 |
| 2015 December | 131 | 0 | 131 |
| 2015 November | 84 | 0 | 84 |
| 2015 October | 70 | 0 | 70 |
| 2015 September | 64 | 0 | 64 |
| 2015 August | 71 | 0 | 71 |
| 2015 July | 67 | 0 | 67 |
| 2015 June | 31 | 0 | 31 |
| 2015 May | 57 | 0 | 57 |
| 2015 April | 6 | 0 | 6 |
Show all
