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1.
Braz J Med Biol Res ; 55: e12284, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36197414

RESUMEN

Amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction. Clinical management depends on the subtype of the protein deposited and the affected organs. Systemic amyloidosis may stem from anomalous proteins, such as immunoglobulin light chains or serum amyloid proteins in chronic inflammation or may arise from hereditary disorders. Hereditary amyloidosis consists of a group of rare conditions that do not respond to chemotherapy, hence the identification of the amyloid subtype is essential for diagnosis, prognosis, and treatment. The kidney is the organ most frequently involved in systemic amyloidosis. Renal amyloidosis is characterized by acellular pathologic Congo red-positive deposition of amyloid fibrils in glomeruli, vessels, and/or interstitium. This disease manifests with heavy proteinuria, nephrotic syndrome, and progression to end-stage kidney failure. In some situations, it is not possible to identify the amyloid subtype using immunodetection methods, so the diagnosis remains indeterminate. In cases where hereditary amyloidosis is suspected or cannot be excluded, genetic testing should be considered. Of note, laser microdissection/mass spectrometry is currently the gold standard for accurate diagnosis of amyloidosis, especially in inconclusive cases. This article reviews the clinical manifestations and the current diagnostic landscape of renal amyloidosis.


Asunto(s)
Amiloidosis Familiar , Amiloidosis , Amiloide , Proteínas Amiloidogénicas , Amiloidosis/diagnóstico , Amiloidosis/patología , Rojo Congo/uso terapéutico , Humanos , Cadenas Ligeras de Inmunoglobulina/uso terapéutico
2.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;55: e12284, 2022. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1403896

RESUMEN

Amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction. Clinical management depends on the subtype of the protein deposited and the affected organs. Systemic amyloidosis may stem from anomalous proteins, such as immunoglobulin light chains or serum amyloid proteins in chronic inflammation or may arise from hereditary disorders. Hereditary amyloidosis consists of a group of rare conditions that do not respond to chemotherapy, hence the identification of the amyloid subtype is essential for diagnosis, prognosis, and treatment. The kidney is the organ most frequently involved in systemic amyloidosis. Renal amyloidosis is characterized by acellular pathologic Congo red-positive deposition of amyloid fibrils in glomeruli, vessels, and/or interstitium. This disease manifests with heavy proteinuria, nephrotic syndrome, and progression to end-stage kidney failure. In some situations, it is not possible to identify the amyloid subtype using immunodetection methods, so the diagnosis remains indeterminate. In cases where hereditary amyloidosis is suspected or cannot be excluded, genetic testing should be considered. Of note, laser microdissection/mass spectrometry is currently the gold standard for accurate diagnosis of amyloidosis, especially in inconclusive cases. This article reviews the clinical manifestations and the current diagnostic landscape of renal amyloidosis.

3.
Clin Exp Immunol ; 177(2): 381-90, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24666423

RESUMEN

Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide exhibiting anti-inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of α-MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an α-MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the α-MSH analogue [Nle4, DPhe7]-α-MSH (NDP-MSH) (1·25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti-nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, α-smooth muscle actin (α-SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin-releasing factor (CRF) and α-MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)-6, IL-10, proteinuria and mesangial cell proliferation together with glomerular expression of α-SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP-MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP-MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of α-SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that α-MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.


Asunto(s)
Lupus Eritematoso Sistémico/metabolismo , alfa-MSH/metabolismo , Animales , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , Artritis/tratamiento farmacológico , Artritis/etiología , Artritis/inmunología , Artritis/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/inmunología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Lupus Eritematoso Sistémico/inducido químicamente , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptor de Melanocortina Tipo 1/metabolismo , Terpenos/efectos adversos , alfa-MSH/administración & dosificación
4.
Lupus ; 23(3): 255-62, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24356611

RESUMEN

Proteinuria is a major feature of lupus nephritis (LN) and reflects podocyte injury. Analysis of podocyte biomarkers was performed attempting to identify if podocyte phenotype is distinct in pure membranous and proliferative LN. Expression of synaptopodin, Wilms tumor protein 1 (WT1), glomerular epithelial protein 1 (GLEPP1) and nephrin was evaluated in 52 LN biopsies by immunohistochemistry. Preserved synaptopodin expression was observed in only 10 (19.2%) of all biopsies while 42 (80.8%) had reduced expression. Both groups had comparable proteinuria at the time of biopsy (p = 0.22); however, in the mean follow-up of four years there was a tendency toward lower mean levels of proteinuria in patients with preserved synaptopodin staining (0.26±0.23 vs. 0.84±0.90 g/24 h, p = 0.05) compared with those with diminished expression. Thirty-nine (75%) biopsies were classified as proliferative and 13 (25%) as pure membranous. Comparison of podocyte biomarkers demonstrated a predominance of preserved staining of synaptopodin (69.2%), WT1 (69.2%), GLEPP1 (53.9%) and nephrin (60%) in the pure membranous group whereas only <10% of the proliferative showed preserved expression. Our data suggest that in proliferative forms there seems to occur structural podocyte damage, whereas in the pure membranous the predominant preserved pattern suggests a dysfunctional podocyte lesion that may account for the better long-term prognosis of proteinuria outcome.


Asunto(s)
Proliferación Celular , Glomerulonefritis Membranoproliferativa/etiología , Glomerulonefritis Membranosa/etiología , Nefritis Lúpica/etiología , Podocitos/patología , Proteinuria/etiología , Adulto , Biomarcadores/análisis , Biopsia , Femenino , Glomerulonefritis Membranoproliferativa/metabolismo , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Humanos , Inmunohistoquímica , Nefritis Lúpica/metabolismo , Nefritis Lúpica/patología , Masculino , Proteínas de la Membrana/análisis , Proteínas de Microfilamentos/análisis , Persona de Mediana Edad , Podocitos/química , Pronóstico , Proteinuria/metabolismo , Proteinuria/patología , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/análisis , Factores de Tiempo , Proteínas WT1/análisis , Adulto Joven
5.
Transplant Proc ; 44(8): 2333-6, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23026586

RESUMEN

Ischemia/reperfusion (I/R) injury remains a major cause of graft dysfunction, which impacts short- and long-term follow-up. Hyperbaric oxygen therapy (HBO), through plasma oxygen transport, has been currently used as an alternative treatment for ischemic tissues. The aim of this study was to analyze the effects of HBO on kidney I/R injury model in rats, in reducing the harmful effect of I/R. The renal I/R model was obtained by occluding bilateral renal pedicles with nontraumatic vascular clamps for 45 minutes, followed by 48 hours of reperfusion. HBO therapy was delivered an hypebaric chamber (2.5 atmospheres absolute). Animals underwent two sessions of 60 minutes each at 6 hours and 20 hours after initiation of reperfusion. Male Wistar rats (n = 38) were randomized into four groups: sham, sham operated rats; Sham+HBO, sham operated rats exposed to HBO; I/R, animals submitted to I/R; and I/R+HBO, I/R rats exposed to HBO. Blood, urine, and kidney tissue were collected for biochemical, histologic, and immunohistochemical analyses. The histopathological evaluation of the ischemic injury used a grading scale of 0 to 4. HBO attenuated renal dysfunction after ischemia characterized by a significant decrease in blood urea nitrogen (BUN), serum creatinine, and proteinuria in the I/R+HBO group compared with I/R alone. In parallel, tubular function was improved resulting in significantly lower fractional excretions of sodium and potassium. Kidney sections from the I/R plus HBO group showed significantly lower acute kidney injury scores compared with the I/R group. HBO treatment significantly diminished proliferative activity in I/R (P < .05). There was no significant difference in macrophage infiltration or hemoxygenase-1 expression. In conclusion, HBO attenuated renal dysfunction in a kidney I/R injury model with a decrease in BUN, serum creatinine, proteinuria, and fractional excretion of sodium and potassium, associated with reduced histological damage.


Asunto(s)
Lesión Renal Aguda/prevención & control , Oxigenoterapia Hiperbárica , Riñón/irrigación sanguínea , Daño por Reperfusión/prevención & control , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores/sangre , Biomarcadores/orina , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Modelos Animales de Enfermedad , Inmunohistoquímica , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Masculino , Potasio/orina , Proteinuria/etiología , Proteinuria/prevención & control , Ratas , Ratas Wistar , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Sodio/orina , Factores de Tiempo
6.
Transplant Proc ; 44(8): 2490-4, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23026627

RESUMEN

BACKGROUND: Chronic allograft vasculopathy (CAV) is an important cause of graft loss. Considering the immune inflammatory events involved in the development of CAV, therapeutic approaches to target this process are of relevance. Human amniotic fluid-derived stem cells (hAFSCs), a class of fetal, pluripotent stem cells with intermediate characteristics between embryonic and adult stem cells, display immunomodulatory properties. hAFSCs express mesenchymal and embryonic markers, show high proliferation rates; however, they do not induce tumor formation, and their use does not raise ethical issues. Thus, we sought to investigate the effect of hAFSC on CAV in a model of aorta transplantation. METHODS: Orthotopic aorta transplantation was performed using Fisher (F344) rats as donors and Lewis rats as recipients. Rats were divided into three groups: syngeneic (SYNG), untreated F344 receiving aorta from F344 (n = 8); allogeneic (ALLO), Lewis rats receiving allogeneic aorta from F344 (n = 8); and ALLO + hAFSC, ALLO rats treated with hAFSC (10(6) cells; n = 8). Histological analysis and immunohistochemistry were performed 30 days posttransplantation. RESULTS: The ALLO group developed a robust aortic neointimal formation (208.7 ± 25.4 µm) accompanied by a significant high number of ED1+ (4845 ± 841 cells/mm2) and CD43+ cells (4064 ± 563 cells/mm2), and enhanced expression of α-smooth muscle actin in the neointima (25 ± 6%). Treatment with hAFSC diminished neointimal thickness (180.7 ± 23.7 µm) and induced a significant decrease of ED1+ (1100 ± 276 cells/mm2), CD43+ cells (1080 ± 309 cells/µm2), and α-smooth muscle actin expression 8 ± 3% in the neointima. CONCLUSIONS: These preliminary results showed that hAFSC suppressed inflammation and myofibroblast migration to the intima, which may contribute to ameliorate vascular changes in CAV.


Asunto(s)
Líquido Amniótico/citología , Aorta Abdominal/trasplante , Enfermedades de la Aorta/prevención & control , Células Madre Fetales/trasplante , Trasplante de Órganos/efectos adversos , Células Madre Pluripotentes/trasplante , Actinas/metabolismo , Animales , Aorta Abdominal/inmunología , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Enfermedades de la Aorta/etiología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Biomarcadores/metabolismo , Movimiento Celular , Células Cultivadas , Células Madre Fetales/inmunología , Células Madre Fetales/metabolismo , Humanos , Inmunohistoquímica , Masculino , Miofibroblastos/metabolismo , Miofibroblastos/patología , Neointima , Células Madre Pluripotentes/inmunología , Células Madre Pluripotentes/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Factores de Tiempo
7.
Transpl Infect Dis ; 13(1): 33-7, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20534038

RESUMEN

Mycobacterium haemophilum is a slow-growing nontuberculous mycobacterium that can cause disease in both immunocompetent and immunocompromised patients. The most common clinical presentations of infection are the appearance of suppurative and ulcerated skin nodules. For the diagnosis, samples collected from suspected cases must be processed under the appropriate conditions, because M. haemophilum requires lower incubation temperatures and iron supplementation in order to grow in culture. In this case report, we describe the occurrence of skin lesions in a kidney transplant recipient, caused by M. haemophilum, associated with acupuncture treatment. The diagnosis was established by direct smear and culture of material aspirated from cutaneous lesions. Species identification was achieved by characterization of the growth requirements and by partial sequencing of the hsp65 gene. The patient was successfully treated with clarithromycin and ciprofloxacin for 12 months. Considering that the number of patients receiving acupuncture treatment is widely increasing, the implications of this potential complication should be recognized, particularly in immunosuppressed patients.


Asunto(s)
Terapia por Acupuntura/efectos adversos , Trasplante de Riñón/efectos adversos , Infecciones por Mycobacterium/microbiología , Mycobacterium haemophilum/aislamiento & purificación , Enfermedades Cutáneas Bacterianas/microbiología , Antibacterianos/uso terapéutico , Ciprofloxacina/uso terapéutico , Claritromicina/uso terapéutico , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/patología , Mycobacterium haemophilum/clasificación , Mycobacterium haemophilum/genética , Enfermedades Cutáneas Bacterianas/diagnóstico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/patología
8.
Transplant Proc ; 42(5): 1659-66, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20620495

RESUMEN

The safety and efficacy of concentration-controlled use of sirolimus (SRL) and cyclosporine (CsA) followed by CsA minimization (CsAm) or elimination (CsAe) beginning at week 13 was compared in a phase 4, open-label, randomized (1:1) trial of renal transplant recipients enrolled between March 2004 and November 2005. The primary endpoint was renal function, measured at 12 months using the Nankivell formula, in patients remaining on therapy. Though a total enrollment of 140 patients in each group was planned to provide an 80% power to detect a difference in means, only 207 subjects were enrolled in this study. Demographic characteristics were similar between groups, with 98.1% recipients of first grafts, 69.1% from living donors, and 7.2% diabetics. At 12 months, there were no differences in renal function (61.08 vs 65.24 mL/min, P = .132); incidence of biopsy-confirmed acute rejection (14.3% vs 22.5%, P = .152); and patient (89.5% vs 92.2%, P = .632), graft (87.6% vs 88.2%, P = .999), and death-censored graft (98.1% vs 94.1%, P = .166) survivals between CsAm and CsAe groups, respectively. There were no differences in the overall rate of study-drug discontinuation (32.4% vs 36.3%, P = .562) but more patients discontinued because of lack of efficacy/graft loss in the CsAe group (4.8% vs 14.7%, P = .018). This study was underpowered to demonstrate the superiority of one regimen over the other. In summary, SRL immunotherapy combined with CsA minimization or elimination showed comparative safety and efficacy. Both regimens offer potential treatment options for de novo renal allograft recipients.


Asunto(s)
Ciclosporina/uso terapéutico , Trasplante de Riñón/inmunología , Sirolimus/uso terapéutico , Adulto , Cadáver , Ciclosporina/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Etnicidad , Femenino , Prueba de Histocompatibilidad , Humanos , Inmunosupresores/uso terapéutico , Pruebas de Función Renal , Trasplante de Riñón/mortalidad , Trasplante de Riñón/fisiología , Donadores Vivos , Masculino , Selección de Paciente , Donantes de Tejidos , Trasplante Homólogo , Insuficiencia del Tratamiento , Resultado del Tratamiento
9.
Am J Transplant ; 10(8): 1918-24, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20636452

RESUMEN

Indoleamine 2,3-dioxygenase (IDO), an enzyme that plays a critical role in fetomaternal tolerance, exerts immunoregulatory functions suppressing T-cell responses. The aims of this study were to promote IDO expression in rat islets using a nonviral gene transfer approach, and to analyze the effect of the in vivo induction of IDO in a model of allogeneic islet transplantation. The IDO cDNA was isolated from rat placenta, subcloned into a plasmid and transfected into rat islets using Lipofectamine. The efficiency of transfection was confirmed by qRT-PCR and functional analysis. The in vivo effect of IDO expression was analyzed in streptozotocin-induced diabetic Lewis rats transplanted with allogeneic islets under the renal capsule. Transplantation of IDO-allogeneic islets reversed diabetes and maintained metabolic control, in contrast to transplantation of allogeneic nontransfected islets, which failed shortly after transplantation in all animals. Graft survival of allograft islets transfected with IDO transplanted without any immunosuppression was superior to that observed in diabetic rats receiving nontransfected islets. These data demonstrated that IDO expression induced in islets by lipofection improved metabolic control of streptozotocin-diabetic rats and prolonged allograft survival.


Asunto(s)
Supervivencia de Injerto/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Trasplante de Islotes Pancreáticos/métodos , Islotes Pancreáticos/enzimología , Animales , Inducción Enzimática , Femenino , Terapia Genética , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Lípidos/administración & dosificación , Liposomas/administración & dosificación , Masculino , Placenta/enzimología , Embarazo , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Transfección
10.
Transplant Proc ; 42(2): 585-8, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20304198

RESUMEN

INTRODUCTION: Chronic allograft vasculopathy is an important cause of graft loss. Considering the inflammatory response in the development of chronic vascular lesions, therapeutic approaches to target the inflammatory process may be useful. We sought to investigate the possible protective effects on balloon catheter-induced vascular injury of thalidomide and tamoxifen, 2 drugs with powerful anti-inflammatory, immunomodulatory, and antifibrotic effects, using an animal model that mimics the morphologic features of chronic allograft vasculopathy. METHODS: Male Wistar rats subjected to balloon catheter carotid injury (INJ) were treated with thalidomide (100 mg/kg), or tamoxifen (10 mg/kg), or vehicle. Contralateral right carotid arteries were used as uninjured controls. Morphometric and immunohistochemical analyses were performed at 14 days postinjury. RESULTS: Injured carotid arteries showed marked neointimal hyperplasia, which was significantly inhibited among animals treated with thalidomide or tamoxifen: neointimal/media ratios of 1.4 +/- 0.4 versus 0.2 +/- 0.1 versus 0.4 +/- 0.2, for INJ, INJ + Thalid, and INJ + Tamox; respectively (P < .001). The endothelial cell loss was significantly less pronounced among animals subjected to carotid balloon injury that were treated with thalidomide (24 +/- 14 vs 1 +/- 1 cells per section in INJ, respectively (P < .05). Therapy with either thalidomide or tamoxifen effectively maintained alpha-smooth muscle actin expression in the media, similar to uninjured arteries. In this setting, tamoxifen was additionally effective to prevent the migration of myofibroblasts in to the intima. CONCLUSION: Thalidomide and tamoxifen were effective to reduce neointimal hyperplasia secondary to vascular damage. The vasculoprotective effects of thalidomide were more pronounced to preserve endothelial cells, whereas tamoxifen inhibited smooth muscle cell migration and proliferation. A possible beneficial effect of combined therapy with thalidomide plus tamoxifen should be addressed in future studies.


Asunto(s)
Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/prevención & control , Hiperplasia/prevención & control , Tamoxifeno/farmacología , Talidomida/farmacología , Túnica Íntima/patología , Animales , Arterias Carótidas/efectos de los fármacos , Hiperplasia/inducido químicamente , Inmunohistoquímica , Masculino , Ratas , Ratas Wistar , Túnica Íntima/efectos de los fármacos , Túnica Íntima/lesiones , Túnica Media/efectos de los fármacos , Túnica Media/lesiones , Túnica Media/patología
11.
Transplant Proc ; 41(3): 862-5, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19376373

RESUMEN

Capillary C4d deposition has been recognized as a marker of antibody-mediated rejection (AMR). Although the detection of capillary C4d by means of immunofluorescence (IF) in cryostat sections is well established, frozen tissue is not always available, thus limiting the diagnosis of AMR. The aim of the present study was to analyze different techniques for C4d staining and the prevalence of C4d in renal allograft biopsies. Detection of C4d was carried out using IF or immunohistochemistry (IHC) on frozen and paraffin sections of renal allograft biopsies available from the same patients. Biopsies obtained from 20 patients were classified into 3 groups: no rejection, acute rejection, and chronic allograft nephropathy (CAN). The capillary C4d deposition prevalence in frozen-IF, considered the gold standard technique for C4d detection, was 45% (9/20 cases). Compared with frozen-IF, the frozen-IHC technique presented an 85% concordance rate (17/20 cases; r = .70; P < .001; sensitivity = 77.8%; specificity = 90.9%). The paraffin-IF technique showed similar results, with an 80% concordance rate (16/20 cases; r = .64; P < .005; sensitivity = 55.6%; specificity = 100%), whereas C4d detection occurred in only 65% of paraffin-IHC cases (13/20; r = .30; not significant; sensitivity = 66.7%; specificity = 63.6%). No capillary C4d deposition was detected in cases without evidence of rejection. However, 4/7 cases (57%) of acute rejection were C4d positive. In the CAN group, 5/11 cases (45%) were C4d positive. In conclusion, these results demonstrated that frozen-IHC and paraffin-IF can be considered alternative techniques to frozen-IF for C4d detection. The paraffin-IHC technique displayed the lowest concordance rate for C4d detection.


Asunto(s)
Complemento C4b/análisis , Rechazo de Injerto/diagnóstico , Trasplante de Riñón/patología , Fragmentos de Péptidos/análisis , Trasplante Homólogo/patología , Adulto , Anticuerpos Monoclonales/sangre , Biopsia , Cadáver , Colorantes , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Humanos , Isoanticuerpos/sangre , Trasplante de Riñón/inmunología , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Donantes de Tejidos , Trasplante Homólogo/inmunología , Adulto Joven
12.
Transplant Proc ; 41(3): 947-51, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19376395

RESUMEN

Stem cells (SC) are potential therapeutic tools in the treatment of chronic renal diseases. Number and engraftment of SC in the injured sites are important for possible differentiation into renal cells and paracrine effect. The aim of this study was to analyze the effect of subcapsular injection of mesenchymal stem cells (MSC) in the 5/6 nephrectomy model (5/6 Nx). MSC obtained from Wistar rats were isolated by their capacity to adhere to plastic surfaces, characterized by flow cytometry, and analyzed by their differentiation potential into osteoblasts. MSC (2 x 10(5)) were injected into the subcapsule of the remnant kidney of male Wistar rats, and were followed for 15 or 30 days. 5/6 Nx rats showed significant hypertension at 15 and 30 days, which was reduced by MSC at 30 days. Increased albuminuria and serum creatinine at 15 and 30 days in 5/6 Nx rats were also reduced by subcapsular injection of MSC. We also observed a significant reduction of glomerulosclerosis index 30 days after injection of MSC. 4-6 diamidino-2-phenylindole dihydrochloride (DAPI)-stained MSC showed a migration of these cells into renal parenchyma 5, 15, and 30 days after subcapsular injection. In conclusion, our data demonstrated that subcapsular injection of MSC in 5/6 Nx rats is associated with renoprotective effects. These results suggest that locally implanted MSC in the kidney allow a large number of cells to migrate into the injured sites and demonstrate that subcapsular injection represent an effective route for MSC delivery.


Asunto(s)
Enfermedades Renales/cirugía , Trasplante de Células Madre Mesenquimatosas/métodos , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Diferenciación Celular , Modelos Animales de Enfermedad , Citometría de Flujo , Glomerulonefritis/cirugía , Inmunofenotipificación , Riñón/cirugía , Masculino , Células Madre Mesenquimatosas/citología , Osteoblastos/citología , Osteogénesis , Ratas , Ratas Wistar
13.
Transplant Proc ; 40(10): 3601-5, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19100448

RESUMEN

Reports on the use of sirolimus (SRL) in pancreas transplantation are still limited. The aim of this study was to evaluate the outcome of SRL conversion in pancreas transplant patients. Among 247 patients undergoing simultaneous kidney-pancreas or solitary pancreas transplantation, 33 (13%) were converted to SRL. The reasons for conversion were calcineurin inhibitors (CNI) nephrotoxicity (n = 24; 73%), severe neurotoxicity owing to CNI (n = 1; 3%), severe and/or recurrent acute rejection episodes (n = 7; 21%), gastrointestinal (GI) side effects of mycophenolate mofetil (MMF; n = 5; 15%), and hyperglycemia (n = 4; 12%). Before conversion, all patients were maintained on a CNI, MMF, and low-dose steroids. They were gradually converted to SRL associated with either CNI or MMF withdrawal. Sixty-three percent (n = 15) of patients who were converted owing to CNI nephrotoxicity, showed stable or improved renal function. At 12 months after conversion, serum creatinine levels were significantly decreased in this group (2.2 +/- 0.5 vs 1.6 +/- 0.3 mg/dL; P = .001) and C-peptide values increased (2.9 +/- 1.1.1 vs 3.1 +/- 1.3 nmol/L; P = .018). The only patient with leucoencephalopathy showed improved neurologic status after SRL conversion. All patients converted to SRL because of GI side effects of MMF showed improvements, and none of those converted because of hyperglycemia experienced improvement. There were no episodes of acute rejection after conversion. We concluded that conversion to SRL in pancreas transplantation should be considered an important alternative strategy, particularly for CNI nephrotoxicity and neurotoxicity, and in cases of severe diarrhea due to MMF.


Asunto(s)
Trasplante de Riñón/inmunología , Trasplante de Páncreas/inmunología , Sirolimus/uso terapéutico , Adulto , Inhibidores de la Calcineurina , Diabetes Mellitus Tipo 1/cirugía , Nefropatías Diabéticas/cirugía , Femenino , Humanos , Hiperglucemia/inducido químicamente , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/análogos & derivados , Estudios Retrospectivos , Adulto Joven
14.
Braz J Med Biol Res ; 40(4): 557-68, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17401500

RESUMEN

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 micro, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5% compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39%; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of betaC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-gamma and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.


Asunto(s)
Lesión Renal Aguda/inmunología , Lesión Renal Aguda/fisiopatología , Linfocitos T CD4-Positivos/inmunología , Daño por Reperfusión/inmunología , Daño por Reperfusión/fisiopatología , Animales , Adhesión Celular/inmunología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Hipoxia/inmunología , Hipoxia/fisiopatología , Riñón/irrigación sanguínea , Riñón/fisiología , Necrosis Tubular Aguda/inmunología , Necrosis Tubular Aguda/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL
15.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;40(4): 557-568, Apr. 2007. graf
Artículo en Inglés | LILACS | ID: lil-445660

RESUMEN

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 æ, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5 percent compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39 percent; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of ßC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-g and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.


Asunto(s)
Animales , Masculino , Ratones , Lesión Renal Aguda , /inmunología , Daño por Reperfusión/inmunología , Daño por Reperfusión/fisiopatología , Hipoxia/inmunología , Hipoxia/fisiopatología , Adhesión Celular/inmunología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Necrosis Tubular Aguda/inmunología , Necrosis Tubular Aguda/fisiopatología , Riñón/irrigación sanguínea , Riñón/fisiología
16.
Transplant Proc ; 39(2): 432-4, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17362749

RESUMEN

Acute allograft rejection represents an important complication after transplantation with significant impact on long-term graft survival. The involvement and relevance of B lymphocytes in this process is still not clear. The aim of this study was to quantify in renal allograft biopsy specimens the number of cells positive for CD20, a specific marker for B lymphocytes. Immunohistochemical techniques using monoclonal anti-CD20 antibody was used on paraffin sections from 38 renal allograft biopsy specimens. The biopsy specimens were classified into 3 groups, according to clinical and histological criteria: normal kidney, acute rejection, and chronic allograft nephropathy (CAN). In the normal kidney, no CD20(+) cells were detected. In contrast, in all cases of acute rejection and CAN, there were CD20(+) cells. The CD20(+) cells occurred in the infiltrate in 2 distinct patterns: scattered or nodular. In cases of acute rejection, the number of CD20(+) cells was significantly higher than in CAN cases (137.0 +/- 57.2 vs 45.4 +/- 9.8 cells/mm(2); P < 0.05). The nodular pattern was observed in 4 of 11 cases (36%) in the acute rejection group, and in 4 of 20 cases (20%) in the CAN cohort. In the acute rejection group, the presence of B-cell clusters tender to be associated with a higher level of serum creatinine (3.7 +/- 1.8 mg/dL vs 2.8 +/- 0.1 mg/dL in the scattered pattern group; not significant [ns]). In conclusion, these preliminary results demonstrated B lymphocytes in cases of renal allograft dysfunction, which were more pronounced in acute allograft rejection. Further analyses are required to determine whether the detection of CD20(+) cells in renal allograft biopsy specimens can be used as a prognostic marker.


Asunto(s)
Antígenos CD20/inmunología , Linfocitos B/inmunología , Trasplante de Riñón/inmunología , Adulto , Anciano , Antígenos CD/inmunología , Biopsia , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Humanos , Trasplante de Riñón/patología , Persona de Mediana Edad , Pronóstico , Trasplante Homólogo
17.
Transplant Proc ; 39(2): 449-52, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17362756

RESUMEN

Sirolimus (SRL) is a potent immunosuppressive drug used in organ transplantation for prophylaxis of acute allograft rejection. Conversion from calcineurin inhibitors to SRL has become an important alternative in patients with chronic allograft nephropathy. Recently, some reports have described the appearance of proteinuria after the use of SRL. The aim of the present study was to describe the incidence of proteinuria in transplant recipients receiving SRL in our transplant center. We studied 78 patients receiving SRL either de novo or after conversion. Eighteen transplant recipients (23.1%) developed proteinuria after SRL treatment. Proteinuria was diagnosed at 11.2 +/- 2.1 months after the initiation of SRL; in eight patients (44.4%) it occurred in the first 6 months. The mean value of proteinuria was 2.6 +/- 0.6 g/24 hours. In 5 patients (27.8%), proteinuria reached nephrotic levels, and in 13 patients (72.2%) was associated with edema. Renal allograft biopsies were performed before conversion to SRL, and a new biopsy, after the appearance of proteinuria. The light microscopy of biopsies performed after the onset of proteinuria showed no specific glomerular changes, except in 2 cases wherein the diagnosis was focal segmental glomerulosclerosis. Immunofluorescence was negative in all cases. In conclusion, in this study proteinuria was observed in 21.3% of patients receiving SRL therapy either as de novo protocol or after conversion to SRL. Proteinuria occurred early after the initiation of SRL therapy and in these cases, withdrawal of SRL was associated with reversion of proteinuria.


Asunto(s)
Inmunosupresores/efectos adversos , Trasplante de Islotes Pancreáticos/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Páncreas/efectos adversos , Proteinuria/epidemiología , Sirolimus/efectos adversos , Adulto , Femenino , Humanos , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Proteinuria/inducido químicamente
18.
Transplant Proc ; 39(2): 467-9, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17362761

RESUMEN

Transplantation of pancreatic islets is a promising therapeutic treatment for type 1 diabetes mellitus. For clinical and experimental transplantation, a large number of pure pancreatic islets are required for transplantation. Thus, the improvement of islet isolation and purification techniques are crucial. In this context, iodixanol-based solution, successfully used for the purification of porcine islets, seems to be a possible alternative to Ficoll for purification of islets. The aim of this study was to test the efficacy of iodixanol compared with Ficoll density gradients for the purification of rat pancreatic islets. Twelve Wistar rats were used for isolation and purification of pancreatic islets. Pancreata were digested with Liberase R1 and islets purified by two gradients: Ficoll or iodixanol gradient. The number and the purity of the pancreatic islets were assessed. To analyze the response of isolated pancreatic islet to glucose challenge, in vitro experiments were performed by measuring the insulin concentration in the Supernatant. The results demonstrated that the iodixanol gradient provided a higher purity of pancreatic islets compared to the Ficoll gradient. In addition, the rat islet yield by iodixanol gradient was significantly higher compared to a Ficoll gradient (751 +/- 16 versus 464 +/- 19 pancreatic islets, respectively; P < .001). The viability of pancreatic islets isolated by an iodixanol gradient was confirmed by high glucose challenge, with more than twofold higher increase in insulin secretion. The present study demonstrated that iodixanol density gradient overcomes Ficoll density gradient, providing a greater number of pure and functional rat pancreatic islets.


Asunto(s)
Medios de Contraste , Islotes Pancreáticos/citología , Ácidos Triyodobenzoicos , Animales , Separación Celular/métodos , Centrifugación por Gradiente de Densidad , Masculino , Ratas , Ratas Wistar
19.
Transplant Proc ; 38(6): 1933-6, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16908327

RESUMEN

UNLABELLED: The optimal immunosuppressive regimen for simultaneous kidney pancreas transplantation (SKPT) is still not established. We conducted a study to compare the safety and efficacy of no induction versus anti-IL-2 receptor induction protocols in SKPT recipients receiving the same maintenance regimen. METHODS: Sixty-three SKPT recipients were divided into two groups: no induction group (n = 42) and anti-IL-2 receptor induction group (n = 21). All patients were maintained on tacrolimus, mycophenolate mofetil, and prednisone. Primary endpoints were 1-year acute rejection incidence and patient and graft survivals. RESULTS: Demographic characteristics were similar between the groups. Acute rejection incidence at 1 year was equal in both groups (28.6%). Kidney and pancreas allograft survival in the no induction group were 78.6% and 76.2%, and in the anti-IL-2R induction group, 81% and 71.4%, respectively (P = NS). Patient survival was also similar: 83.3% in the no induction versus 85.7% in the anti-IL-2R induction group. Deaths due to sepsis were higher in the anti-IL-2R induction group, albeit not significantly. CONCLUSION: The use of a no-induction protocol in SKPT is safe and effective immunosuppression that also reduces transplantation costs.


Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Trasplante de Páncreas/inmunología , Receptores de Interleucina-2/inmunología , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Biopsia , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/prevención & control , Daclizumab , Quimioterapia Combinada , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Inmunoglobulina G/uso terapéutico , Terapia de Inmunosupresión/métodos , Trasplante de Riñón/mortalidad , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Trasplante de Páncreas/mortalidad , Selección de Paciente , Prednisona/uso terapéutico , Análisis de Supervivencia
20.
Nephron Physiol ; 101(4): p82-91, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16113589

RESUMEN

BACKGROUND: Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27. METHODS: Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-beta1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA). RESULTS: SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 +/- 7.3 vs. 84.4 +/- 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-beta did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 +/- 6.6 vs. 50.2 +/- 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 +/- 0.40 vs. 4.07 +/- 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV. CONCLUSION: SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/patología , Simvastatina/farmacología , Albuminuria/inmunología , Albuminuria/patología , Animales , División Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Matriz Extracelular/fisiología , Hipertensión Renal/inmunología , Linfocitos/metabolismo , Linfocitos/patología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , ARN Mensajero/análisis , Ratas , Ratas Wistar , Cloruro de Sodio/farmacología , Factor de Crecimiento Transformador beta/genética
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