Use of sirolimus in patients with primary steroid-resistant nephrotic syndrome
Uso del sirolimus en pacientes con síndrome nefrótico córtico-resistente primario
Miguel Lierna, Miguel Liernb, Veronica Dereyesa, Verónica Dereyesb, Alicia Fayadc, Graciela Vallejoc
a Unidad de Nefrología, Hospital de Niños Ricardo Gutierrez, ´CABA, Buenos Aires, Argentina,
b Unidad de Nefrología, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina,
c Unidad de Nefrología, Hospital de Niños Ricardo Gutierrez, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina,
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"Fayad" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 5 => array:3 [ "nombre" => "Graciela" "apellidos" => "Vallejo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unidad de Nefrología, Hospital de Niños Ricardo Gutierrez, ´CABA, Buenos Aires, Argentina, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Unidad de Nefrología, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Unidad de Nefrología, Hospital de Niños Ricardo Gutierrez, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Uso del sirolimus en pacientes con síndrome nefrótico córtico-resistente primario" ] ] "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" => "11093_16025_29477_en_t1_11093.jpg" "Alto" => 980 "Ancho" => 2148 "Tamanyo" => 553241 ] ] "descripcion" => array:1 [ "en" => "Therapy and time elapsed before start of treatment with sirolimus" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Steroid-resistant nephrotic syndrome (SRNS) can lead to chronic renal failure.<span class="elsevierStyleSup">1,2</span> Proteinuria values in the nephrotic range provide a good marker for renal damage, and reducing these values is correlated with preserved glomerular filtration rate.<span class="elsevierStyleSup">3,4</span></p><p class="elsevierStylePara">The massive flow of proteins to the mesangium causes cell proliferation and the activation of chemotactic factors, with a consequent progression towards extrinsic compression of the glomerular vessels, finally leading to global and diffuse glomerulosclerosis.<span class="elsevierStyleSup">5,6</span> In order to avoid this progression, several different therapeutic options have been employed (cyclophosphamide [CPM], sodium mycophenolate, cyclosporine [CsA], levamisole, tacrolimus, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARB], etc.), in some cases with fairly unsatisfactory results and severe toxic effects.<span class="elsevierStyleSup">7-11</span></p><p class="elsevierStylePara">We designed a treatment protocol for sirolimus (mTOR inhibitor with antiproliferative effects) for primary nephrotic patients with focal segmental glomerulosclerosis (FSGS) that are unresponsive to normal treatment.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">OBJECTIVES</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The primary objective was to evaluate the reduction of proteinuria in patients with primary SRNS treated with sirolimus.</p><p class="elsevierStylePara">Secondary objectives included: 1) evaluate the correlation between response to treatment and time elapsed from the clinical diagnosis of nephrotic syndrome to treatment with sirolimus; 2) evaluate the relationship between histological damage at the start of treatment and the type of response to treatment.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">MATERIAL AND METHOD </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">We performed a prospective, interventional, non-randomised intra-subject study, using a cohort series of 13 patients with a mean age of 10 years (range: 8-18 years) who had primary SRNS resistant to calcineurin inhibitors (CsA, tacrolimus), and cyclophosphamide. They did not respond to enalapril (EN) or losartan (LO) treatment either.</p><p class="elsevierStylePara">We defined nephrotic syndrome as proteinuria >40mg/m<span class="elsevierStyleSup">2</span>/hour, hypoalbuminaemia <2.5g%, and frequent hypercholesterolemia above the 95<span class="elsevierStyleSup">th</span> percentile for the patient’s sex and age group.<span class="elsevierStyleSup">12</span> We defined SRNS as persistent nephrotic syndrome after having completed 4 weeks of treatment with meprednisone at 48mg/m<span class="elsevierStyleSup">2</span>/day (steroid dose equivalent to 60mg/m<span class="elsevierStyleSup">2</span>/day of prednisone), followed by 3 consecutive pulses of 16-beta-methylprednisolone at 15mg/kg/dose.<span class="elsevierStyleSup">13,14</span></p><p class="elsevierStylePara">Patients were biopsied before starting treatment with CsA, and the pathological diagnosis of FSGS was defined as at least one glomerulus with a segmental lesion, which in turn was defined as the existence of at least one lobule with capillary scarring in the glomerulus examined. The diagnosis was considered to be primary in the absence of immunopathological or ultrastructural evidence of other coexisting glomerular diseases, or in the absence of a systemic disease associated with FSGS. It was not possible to perform genetic analyses of any of the patients studied.</p><p class="elsevierStylePara">Inclusion criteria were: nephrotic syndrome with primary FSGS, negative pregnancy test, and approved medical consent. The exclusion criteria were: creatinine clearance (CCr) <60ml/min/1.73m<span class="elsevierStyleSup">2</span>, gastric or duodenal ulcers, active tumours and/or infections with or without specific treatment, diabetes, morbid obesity, vesicoureteral reflux, single kidney, or intravenous drug abuse. Finally, the criteria for interrupting treatment were a reduction in CCr>30% from initial levels for a period >3 months, leukopenia (leukocyte count <3000/mm<span class="elsevierStyleSup">3</span>), refractory anaemia, active infection, persistent gastrointestinal intolerance, or lack of response in proteinuria reduction, <50% from initial values, after 6 months of treatment.</p><p class="elsevierStylePara">The variables evaluated included: nephrotic proteinuria, severity of the initial histological lesion, adverse events related to treatment with sirolimus, and time elapsed between establishing the clinical diagnosis and starting treatment with sirolimus.</p><p class="elsevierStylePara">In order to evaluate the efficacy of treatment, we established three different levels of therapeutic response: 1) total response: reduction in proteinuria <4mg/m<span class="elsevierStyleSup">2</span>/hour; partial response: reduction in proteinuria of 4-40mg/m<span class="elsevierStyleSup">2</span>/hour; and no response: persistent nephrotic proteinuria >40mg/m<span class="elsevierStyleSup">2</span>/hour.</p><p class="elsevierStylePara">All histological lesions were classified by the same pathologist, who established the severity of histological renal damage according to medical literature values<span class="elsevierStyleSup">15</span> and personal experience, establishing a scale of 0-3 (absent, mild, moderate, and severe) for glomerular sclerosis, interstitial fibrosis, and vascular atrophy, respectively. Based on the level of sensitivity and specificity for each histological variable measured, a score >6 was considered to be indicative of high risk. We also evaluated the time elapsed between the clinical diagnosis of nephrotic syndrome and the start of treatment with sirolimus.</p><p class="elsevierStylePara">The 13 patients were receiving EN at the start of the study, with a dosage range of 0.1-0.3mg/kg/day, and LO at a dose of 0.8-1.5mg/kg/day. Sirolimus was administered at 1-5mg/m<span class="elsevierStyleSup">2</span>/day (maximum dose of 5mg/day) once a day, maintaining a whole blood concentration of 7-10ng/ml.</p><p class="elsevierStylePara">We took monthly blood samples and tested for: creatinine (calculating CCr using the Schwartz method) uraemia, complete haemogram, cholesterolemia, triglyceridemia, LDL cholesterol (low-density lipoprotein), HDL cholesterol (high-density lipoprotein), protein electrophoresis, serum amylase, blood uric acid, serum lipase, hepatogram, serum electrolytes, and sirolimus levels in whole blood samples. We also measured urine electrolytes, proteinuria/day, and urine urea in urine samples.</p><p class="elsevierStylePara">If adverse events occurred related to the treatment provided, the following measures were taken:</p><p class="elsevierStylePara">-25% reduction of the initial sirolimus dose</p><p class="elsevierStylePara">-Treatment of symptoms,</p><p class="elsevierStylePara">-Return to initial drug dose once symptoms disappeared.</p><p class="elsevierStylePara">The statistical methods used for analysing the data were:</p><p class="elsevierStylePara">-Wilcoxon test for evaluating the probability of response based on the type of therapy employed and variation in proteinuria,</p><p class="elsevierStylePara">-Multiple regression analysis to evaluate the relationship between each variable evaluated (tubular atrophy, interstitial fibrosis, glomerular sclerosis, time elapsed between the clinical diagnosis of nephrotic syndrome and the start of therapy, and proteinuria prior to treatment) and variation in proteinuria during the study.</p><p class="elsevierStylePara">A <span class="elsevierStyleItalic">P</span>-value <0.05 was considered to be statistically significant. Results were expressed as mean ± SD. We used SPSS statistical software, version 13.0, for all analyses.</p><p class="elsevierStylePara">We obtained informed consent from all patients prior to inclusion in the study, and all steps of the treatment protocol were evaluated and approved by the ethics and research committee at our hospital. There were no conflicts of interest.</p><p class="elsevierStylePara">Treatment lasted a total of 12 months, and the last check-up was performed 26 months after treatment had commenced.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Upon completing the study, 9/13 patients had responded to treatment; of them, 5 had complete remission of disease and 4 had a partial response. The Wilcoxon test showed very significant results (<span class="elsevierStyleItalic">P</span>=.0002). The mean pre-treatment value for proteinuria in the 9 patients that responded was 212mg/m<span class="elsevierStyleSup">2</span>/hour (SD: 20), and the mean post-treatment value in the 4 patients with a partial response was 18mg/m<span class="elsevierStyleSup">2</span>/hour (SD: 3), with a 92% reduction in proteinuria. The 5 patients with a complete response had a mean post-treatment proteinuria value of 3mg/m<span class="elsevierStyleSup">2</span>/hour (SD: 1), a 99% reduction in proteinuria (Figure 1).</p><p class="elsevierStylePara">The mean pre-treatment proteinuria value in the 4 unresponsive patients was 226mg/m<span class="elsevierStyleSup">2</span>/hour (SD: 22) and the post-treatment value was 79mg/m<span class="elsevierStyleSup">2</span>/hour (SD: 27). This corresponded to a 65% reduction.</p><p class="elsevierStylePara">During the 12 months of treatment, 2 of the patients with a partial response suffered recurrences. Both reached a partial response again after receiving traditional steroid treatment, with no changes at 1 year.</p><p class="elsevierStylePara">Of all the variables evaluated, the time at which sirolimus was started (a mean 21.2 months for total response patients, 25 months for partial response, and 31.5 months for no response; R2: 0.70) and tubular atrophy (R2: 0.72) had a strong correlation with variation in proteinuria for all three response types (Table 1).</p><p class="elsevierStylePara">On the other hand, only mild correlations were observed for interstitial fibrosis (R2: 0.52) and glomerular sclerosis (R2: 0.52), and low correlations were observed for pre-treatment proteinuria levels (R2: 0.38) (<span class="elsevierStyleItalic">P</span>=.01) (Table 2).</p><p class="elsevierStylePara">The mean dose of sirolimus was 3.6mg/m<span class="elsevierStyleSup">2</span>/day (3.1mg/m<span class="elsevierStyleSup">2</span>/day for total response patients, 3.5mg/m<span class="elsevierStyleSup">2</span>/day for partial response patients, and 5.8mg/m<span class="elsevierStyleSup">2</span>/day for unresponsive patients).</p><p class="elsevierStylePara">The mean EN dose was 0.18mg/kg/day (0.18mg/kg/day for total response, 0.16mg/kg/day for partial response, and 0.20mg/kg/day for no response). The mean dose of LO was 1.1mg/kg/day (1.1mg/kg/day for total response, 1.2mg/kg/day for partial response, and 1.2mg/kg/day for no response).</p><p class="elsevierStylePara">The mean whole blood concentration of sirolimus was 8.4ng/ml (7.7ng/ml for total response, 8.5ng/ml for partial response, and 9ng/ml for no response) (Table 3).</p><p class="elsevierStylePara">The following is a description of the adverse events:</p><p class="elsevierStylePara">- Anaemia: Three patients. Two patients had low ferritin levels and responded well to treatment with ferrous sulphate, and the others had normal ferritin levels but inadequate transferrin saturation levels. This patient improved after receiving ferrous sulphate at 7mg/kg/day and 5mg/day of folic acid.</p><p class="elsevierStylePara">- Acute diarrhoea: Two patients responded well to a temporary dosage reduction of sirolimus and a diet low in fermented foods.</p><p class="elsevierStylePara">- Mouth ulcers: Three patients went into remission following oral rinses with sucralfate and did not require suspension of sirolimus treatment (Figure 2).</p><p class="elsevierStylePara">No significant differences were observed in the doses or whole blood levels of sirolimus between patients with and without adverse effects. No other adverse effects occurred that could have been correlated with treatment.</p><p class="elsevierStylePara">Throughout the study period, 13 patients had the following mean blood pressure values: 77±5mm Hg for total response, 74±5mm Hg for partial response, and 77±5mm Hg for no response. Serum creatinine values were: 0.8±0.1mg/dl for total response, 0.9±0.2mg/dl for partial response, and 0.8±0.1mg/dl for no response.</p><p class="elsevierStylePara">The 13 patients completed the 12 month treatment protocol, including the 4 that remained within the nephrotic range, since they still underwent a reduction in proteinuria >50% as compared to initial values. Of the 9 patients that responded to treatment, 8 had varying values of proteinuria, but had no relapses by the last check-up performed after 26 months. The 4 unresponsive patients remain within the nephrotic syndrome and have normal glomerular filtration rates (Table 4).</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">By the time the last control check-up was performed, none of the 13 patients had undergone another biopsy.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In our study, proteinuria values decreased by more than 90% in 9 of 13 patients. With this substantial decrease, the nephrotic syndrome went into remission in 5 patients, and the other 4 continued with significant proteinuria; even the 4 children that continued to have massive proteinuria experienced a decrease >50% from initial values. Similar results were described in a study by Tumlin,<span class="elsevierStyleSup">16</span> after 6 months of treatment with sirolimus.</p><p class="elsevierStylePara">The management of SRNS is a challenging health situation. Approximately 80% of patients with primary nephrotic syndrome respond to steroid treatment, and the combined use of cytotoxic drugs generally improves the rate of remission<span class="elsevierStyleSup">1,3</span>; however, the remaining 20% may require other treatment regimens. This can result in very high rates of adverse effects,<span class="elsevierStyleSup">4,5</span> motivating the search for other treatment alternatives that can reduce proteinuria, even if complete recovery from renal damage is not an option. Several different alternative methods have been tested (steroids, CPM, CsA, tacrolimus, ACE inhibitors, ARB, etc.) in monotherapy and combined therapy, although results are often less than satisfactory.<span class="elsevierStyleSup">16,17</span></p><p class="elsevierStylePara">The use of CsA and tacrolimus-based treatment can result in<span class="elsevierStyleSup">14,18,19</span> remission rates as high as 70%, although many of the patients treated with these drugs then suffer relapses within 6 months after completing the treatment regimen. In order to avoid this large number of recurrences, treatment periods have been extended, which involves an increased risk of nephrotoxicity.<span class="elsevierStyleSup">18</span></p><p class="elsevierStylePara">Sirolimus is a new immunosuppressant that blocks T-cell proliferation and has a similar structure to tacrolimus, binding to the same immunomodulators without affecting the activity of calcineurin. At therapeutic doses, sirolimus blocks the proliferation of T-cells in the G1-S phase. This mechanism probably reduces structural alteration of podocytes in FSGS.<span class="elsevierStyleSup">19,20</span></p><p class="elsevierStylePara">Few studies have been published on the mechanism of action of rapamycin in these glomerulopathies, and the main objections are its potential long-term toxic effects.<span class="elsevierStyleSup">21,22</span> One of the most commonly mentioned sides effects is anaemia, with reduced haematocrit in 50% of the treated population. This type of anaemia can be caused by several different mechanisms, such as the drug interfering with the proliferation of primitive erythroid cells.<span class="elsevierStyleSup">23,24</span> Three of our patients developed iron-deficiency anaemia, which was effectively treated with ferrous sulphate and folic acid; we did not need to administer erythropoietin to any of our patients.</p><p class="elsevierStylePara">A causative relationship has been described between sirolimus and hyperlipidaemia, characterised by increased total and LDL cholesterol, apo-B100, apoC-III, free fatty acids, and triglycerides.<span class="elsevierStyleSup">25,26</span> In our study sample, hyperlipidaemia was present prior to starting the treatment protocol, which is frequently observed in nephrotic syndrome. However, considering the reduction in lipid levels observed in the group that went into remission, we were unable to establish a causative relationship between the use of sirolimus and hyperlipidaemia.</p><p class="elsevierStylePara">With regard to the eventual development of pathological proteinuria and renal failure due to a hyperfiltration mechanism caused by the use of sirolimus, whether in the form of haemodynamic changes (increased renal blood flow and intraglomerular pressure)<span class="elsevierStyleSup">27</span> or an unknown mechanism of nephrotoxicity, Fervenza<span class="elsevierStyleSup">21</span> reported worsening renal failure (from a pre-existing condition) in 6 of 11 patients diagnosed with FSGS, IgA nephropathy, and primary membranous glomerulonephritis, all treated with sirolimus. Letavernier described adult recipients that developed FSGS with consequent nephrotic syndrome after receiving high doses of sirolimus.<span class="elsevierStyleSup">28</span> In a study by Cho,<span class="elsevierStyleSup">29</span> 0 out of 5 adult patients treated with sirolimus had a total or partial remission of nephrotic syndrome, and treatment had to be suspended due to the appearance of adverse effects (decreased glomerular filtration rate and hyperlipidaemia). In contrast, none of our patients suffered renal function deterioration (the fact that they started the treatment regimen with normal glomerular filtration rates was probably an important factor for patient evolution). Furthermore, proteinuria decreased in all of them, although not always to the same extent.</p><p class="elsevierStylePara">Diarrhoea is another potential adverse effect.<span class="elsevierStyleSup">30</span> In our study, three children suffered acute diarrhoea, abdominal pain, nausea, and vomiting during the treatment period, but responded rapidly to a temporary reduction in the dose of sirolimus and proper diet. The eventual appearance of mouth lesions (ulcers, glossitis, gingivitis, etc.) can occur in patients receiving sirolimus (apparently depending on the dosage). The majority of these diagnoses were made according to clinical criteria (not microbiological), and it has been proven that a reduced dose or temporary suspension of treatment can be used to minimise these effects. In addition, symptomatic treatment appears to improve the symptoms.<span class="elsevierStyleSup">31</span> Three of our patients developed mouth ulcers, which disappeared after administering oral rinses with sucralfate and did not require reducing the dose of sirolimus.</p><p class="elsevierStylePara">The available medical literature highlight the moment of diagnosis and an early start of treatment as factors influencing the failure of SRNS treatment.<span class="elsevierStyleSup">32-34 </span>In agreement with other results, we observed that the time elapsed before administering sirolimus and the severity of histological lesions prior to treatment had an impact on the response to treatment. However, we must admit that our inability to perform genetic tests for nephrotic syndrome impeded the analysis of this important variable. We believe that the two factors are inter-related, possibly promoting the progressive development of non-immunological proteinuria, which is present in the process of hyperfiltration that damages the remaining nephrons. As such, we maintained EN and LO in combination throughout the treatment regimen. The addition of this combined therapy to sirolimus is justified in the haemodynamic and molecular mechanisms of ACE inhibitors and ARB, resulting in a decrease in the diffusion gradients and, eventually, reduced proteinuria.<span class="elsevierStyleSup">35,36</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">We believe that sirolimus is a valid treatment option for patients with SRNS, although an earlier start to treatment is probably necessary. Future studies could contribute to clarifying this issue.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors affirm that they have no conflicts of interest related to the content of this article.</p><p class="elsevierStylePara"><a href="grande/11093_16025_29477_en_t1_11093.jpg" class="elsevierStyleCrossRefs"><img src="11093_16025_29477_en_t1_11093.jpg" alt="Therapy and time elapsed before start of treatment with sirolimus"></img></a></p><p class="elsevierStylePara">Table 1. Therapy and time elapsed before start of treatment with sirolimus</p><p class="elsevierStylePara"><a href="grande/11093_16025_29478_en_t2_11093.jpg" class="elsevierStyleCrossRefs"><img src="11093_16025_29478_en_t2_11093.jpg" alt="Relationship between histological damage and time elapsed to use of sirolimus and variation in proteinuria"></img></a></p><p class="elsevierStylePara">Table 2. Relationship between histological damage and time elapsed to use of sirolimus and variation in proteinuria</p><p class="elsevierStylePara"><a href="grande/11093_16025_29479_en_t3_11093.jpg" class="elsevierStyleCrossRefs"><img src="11093_16025_29479_en_t3_11093.jpg" alt="Final proteinuria values, dosage, and whole blood levels of sirolimus"></img></a></p><p class="elsevierStylePara">Table 3. Final proteinuria values, dosage, and whole blood levels of sirolimus</p><p class="elsevierStylePara"><a href="grande/11093_16025_29480_en_t4_110936.jpg" class="elsevierStyleCrossRefs"><img src="11093_16025_29480_en_t4_110936.jpg" alt="Variation between laboratory values diagnostic of nephrotic syndrome and creatinine clearance from the start of the treatment protocol until the last post-treatment check-up"></img></a></p><p class="elsevierStylePara">Table 4. Variation between laboratory values diagnostic of nephrotic syndrome and creatinine clearance from the start of the treatment protocol until the last post-treatment check-up</p><p class="elsevierStylePara"><a href="grande/11093_16025_29481_en_f1_11093.jpg" class="elsevierStyleCrossRefs"><img src="11093_16025_29481_en_f1_11093.jpg" alt="Variation in proteinuria values in patients that responded to treatment"></img></a></p><p class="elsevierStylePara">Figure 1. Variation in proteinuria values in patients that responded to treatment</p><p class="elsevierStylePara"><a href="grande/11093_16025_29482_en_f2_11093.jpg" class="elsevierStyleCrossRefs"><img src="11093_16025_29482_en_f2_11093.jpg" alt="Adverse events: time to appearance, dosage, and blood levels of sirolimus"></img></a></p><p class="elsevierStylePara">Figure 2. Adverse events: time to appearance, dosage, and blood levels of sirolimus</p>" "pdfFichero" => "P1-E536-S3491-A11093-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438301" "palabras" => array:1 [ 0 => "Focal y segmentaria" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438303" "palabras" => array:1 [ 0 => "Sirolimus" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438305" "palabras" => array:1 [ 0 => "Síndrome nefrótico córtico-resistente" ] ] ] "en" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438302" "palabras" => array:1 [ 0 => "Focal and segmental" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438304" "palabras" => array:1 [ 0 => "Sirolimus" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438306" "palabras" => array:1 [ 0 => "Steroid-resistant nephrotic syndrome" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">La persistencia de la proteinuria nefrótica favorece la progresión hacia la insuficiencia renal. Hemos diseñado un protocolo terapéutico con sirolimus para ese grupo de pacientes implementando un estudio clínico prospectivo, intervencionista y no aleatorizado, sobre una cohorte de 13 pacientes con una edad media de 10 años; todos con síndrome nefrótico córtico-resistente primario y glomerulosclerosis focal y segmentaria; resistentes también a la ciclofosfamida, a los inhibidores de la calcineurina y al empleo de enalapril y losartán. La dosis media empleada de sirolimus fue de 3,6 mg/m<span class="elsevierStyleSup">2</span>/día y el tratamiento duró 12 meses. Evaluamos la eficacia terapéutica acorde a la reducción de la proteinuria (respuesta total, parcial y ausente), y también fueron evaluadas la severidad del daño histológico pretratamiento y el tiempo previo transcurrido hasta recibir el sirolimus. Nueve de los trece pacientes tuvieron remisión parcial o total del síndrome nefrótico, y el tiempo medio previo transcurrido y la severidad del daño histológico influyeron en el tipo de respuesta. Consideramos que el sirolimus es una opción válida de tratamiento para los pacientes con síndrome nefrótico córtico-resistente, aunque probablemente sea necesario un inicio terapéutico más precoz.</p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Persistent nephrotic syndrome that does not respond to treatment may cause progression to kidney failure. We designed a therapeutic protocol with sirolimus for this group of patients. We conducted a prospective, interventional, time series, cohort study lasting 20 months. Thirteen patients were enrolled, with a mean age of 10 years (range: 8-18 years old) with steroid-resistant primary nephrotic syndrome and a histological diagnosis of focal and segmental glomerulosclerosis. We administered sirolimus 3.6mg/m<span class="elsevierStyleSup">2</span>/day. The duration of this regimen was 12 months in responsive patients. The protocol’s efficacy was assessed according to reduction of proteinuria (3 response levels: total, partial, or no response). Severity of histological renal damage and mean time from clinical diagnosis to protocol initiation were also assessed. Nine of 13 patients responded to the treatment with sirolimus, and mean progression time and the severity of histological renal damage influenced response to therapy. We believe that sirolimus is a valid treatment option in patients with steroid-resistant nephrotic syndrome, even though this regimen probably requires an earlier treatment<span class="elsevierStyleBold">.</span></p>" ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11093_16025_29477_en_t1_11093.jpg" "Alto" => 980 "Ancho" => 2148 "Tamanyo" => 553241 ] ] "descripcion" => array:1 [ "en" => "Therapy and time elapsed before start of treatment with sirolimus" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11093_16025_29478_en_t2_11093.jpg" "Alto" => 934 "Ancho" => 2148 "Tamanyo" => 432970 ] ] "descripcion" => array:1 [ "en" => "Relationship between histological damage and time elapsed to use of sirolimus and variation in proteinuria" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Tab. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11093_16025_29479_en_t3_11093.jpg" "Alto" => 909 "Ancho" => 2156 "Tamanyo" => 480632 ] ] "descripcion" => array:1 [ "en" => "Final proteinuria values, dosage, and whole blood levels of sirolimus" ] ] 3 => array:8 [ "identificador" => "fig4" "etiqueta" => "Tab. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11093_16025_29480_en_t4_110936.jpg" "Alto" => 1059 "Ancho" => 2178 "Tamanyo" => 729205 ] ] "descripcion" => array:1 [ "en" => "Variation between laboratory values diagnostic of nephrotic syndrome and creatinine clearance from the start of the treatment protocol until the last post-treatment check-up" ] ] 4 => array:8 [ "identificador" => "fig5" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11093_16025_29481_en_f1_11093.jpg" "Alto" => 947 "Ancho" => 1011 "Tamanyo" => 247528 ] ] "descripcion" => array:1 [ "en" => "Variation in proteinuria values in patients that responded to treatment" ] ] 5 => array:8 [ "identificador" => "fig6" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11093_16025_29482_en_f2_11093.jpg" "Alto" => 896 "Ancho" => 1010 "Tamanyo" => 174671 ] ] "descripcion" => array:1 [ "en" => "Adverse events: time to appearance, dosage, and blood levels of sirolimus" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "1.\u{A0}\u{A0} \u{A0}Srivastava T, Somon SD. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 13 | 23 |
| 2024 October | 59 | 48 | 107 |
| 2024 September | 72 | 32 | 104 |
| 2024 August | 91 | 76 | 167 |
| 2024 July | 66 | 36 | 102 |
| 2024 June | 98 | 56 | 154 |
| 2024 May | 88 | 39 | 127 |
| 2024 April | 76 | 45 | 121 |
| 2024 March | 48 | 27 | 75 |
| 2024 February | 58 | 38 | 96 |
| 2024 January | 47 | 24 | 71 |
| 2023 December | 42 | 31 | 73 |
| 2023 November | 85 | 54 | 139 |
| 2023 October | 50 | 38 | 88 |
| 2023 September | 45 | 28 | 73 |
| 2023 August | 61 | 24 | 85 |
| 2023 July | 64 | 35 | 99 |
| 2023 June | 55 | 34 | 89 |
| 2023 May | 65 | 37 | 102 |
| 2023 April | 43 | 18 | 61 |
| 2023 March | 67 | 23 | 90 |
| 2023 February | 55 | 24 | 79 |
| 2023 January | 53 | 36 | 89 |
| 2022 December | 65 | 27 | 92 |
| 2022 November | 75 | 38 | 113 |
| 2022 October | 50 | 37 | 87 |
| 2022 September | 63 | 34 | 97 |
| 2022 August | 59 | 48 | 107 |
| 2022 July | 55 | 54 | 109 |
| 2022 June | 65 | 39 | 104 |
| 2022 May | 48 | 48 | 96 |
| 2022 April | 48 | 53 | 101 |
| 2022 March | 59 | 67 | 126 |
| 2022 February | 48 | 39 | 87 |
| 2022 January | 87 | 36 | 123 |
| 2021 December | 57 | 42 | 99 |
| 2021 November | 72 | 37 | 109 |
| 2021 October | 62 | 42 | 104 |
| 2021 September | 60 | 49 | 109 |
| 2021 August | 39 | 65 | 104 |
| 2021 July | 50 | 34 | 84 |
| 2021 June | 57 | 23 | 80 |
| 2021 May | 54 | 39 | 93 |
| 2021 April | 97 | 64 | 161 |
| 2021 March | 59 | 45 | 104 |
| 2021 February | 54 | 23 | 77 |
| 2021 January | 59 | 18 | 77 |
| 2020 December | 41 | 18 | 59 |
| 2020 November | 56 | 20 | 76 |
| 2020 October | 34 | 18 | 52 |
| 2020 September | 35 | 6 | 41 |
| 2020 August | 61 | 17 | 78 |
| 2020 July | 55 | 5 | 60 |
| 2020 June | 47 | 19 | 66 |
| 2020 May | 115 | 14 | 129 |
| 2020 April | 59 | 15 | 74 |
| 2020 March | 45 | 12 | 57 |
| 2020 February | 69 | 21 | 90 |
| 2020 January | 59 | 20 | 79 |
| 2019 December | 70 | 32 | 102 |
| 2019 November | 54 | 20 | 74 |
| 2019 October | 61 | 18 | 79 |
| 2019 September | 66 | 23 | 89 |
| 2019 August | 32 | 16 | 48 |
| 2019 July | 59 | 26 | 85 |
| 2019 June | 59 | 21 | 80 |
| 2019 May | 59 | 15 | 74 |
| 2019 April | 118 | 48 | 166 |
| 2019 March | 80 | 23 | 103 |
| 2019 February | 45 | 20 | 65 |
| 2019 January | 62 | 23 | 85 |
| 2018 December | 122 | 46 | 168 |
| 2018 November | 104 | 15 | 119 |
| 2018 October | 95 | 12 | 107 |
| 2018 September | 137 | 20 | 157 |
| 2018 August | 95 | 20 | 115 |
| 2018 July | 70 | 27 | 97 |
| 2018 June | 84 | 15 | 99 |
| 2018 May | 83 | 16 | 99 |
| 2018 April | 105 | 10 | 115 |
| 2018 March | 92 | 6 | 98 |
| 2018 February | 80 | 4 | 84 |
| 2018 January | 107 | 10 | 117 |
| 2017 December | 86 | 11 | 97 |
| 2017 November | 105 | 12 | 117 |
| 2017 October | 72 | 11 | 83 |
| 2017 September | 74 | 9 | 83 |
| 2017 August | 53 | 15 | 68 |
| 2017 July | 65 | 11 | 76 |
| 2017 June | 83 | 18 | 101 |
| 2017 May | 121 | 12 | 133 |
| 2017 April | 64 | 18 | 82 |
| 2017 March | 112 | 13 | 125 |
| 2017 February | 173 | 13 | 186 |
| 2017 January | 80 | 17 | 97 |
| 2016 December | 112 | 8 | 120 |
| 2016 November | 168 | 15 | 183 |
| 2016 October | 229 | 9 | 238 |
| 2016 September | 352 | 9 | 361 |
| 2016 August | 359 | 10 | 369 |
| 2016 July | 307 | 15 | 322 |
| 2016 June | 192 | 0 | 192 |
| 2016 May | 177 | 0 | 177 |
| 2016 April | 171 | 0 | 171 |
| 2016 March | 111 | 0 | 111 |
| 2016 February | 138 | 0 | 138 |
| 2016 January | 119 | 0 | 119 |
| 2015 December | 134 | 0 | 134 |
| 2015 November | 128 | 0 | 128 |
| 2015 October | 139 | 0 | 139 |
| 2015 September | 95 | 0 | 95 |
| 2015 August | 100 | 0 | 100 |
| 2015 July | 154 | 0 | 154 |
| 2015 June | 44 | 0 | 44 |
| 2015 May | 58 | 0 | 58 |
| 2015 April | 6 | 0 | 6 |
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