RESUMEN
OBJECTIVE: The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy. METHODS: This is a two-center retrospective cohort study. Patients of idiopathic membranous nephropathy were enrolled and divided into two groups with or without focal segmental glomerulosclerosis lesions according to the renal biopsy. Laboratory data and pathological manifestation were compared. Renal phospholipase A2 receptor was detected by immunofluorescence. During the follow-up, the effects of different therapies and renal function were estimated. RESULTS: A total of 236 patients were finally enrolled in this study, of which 60 and 176 idiopathic membranous nephropathy patients were enrolled in the FSGS+ and FSGS- groups, respectively. The FSGS+ group showed a higher percentage of hypertension history (38.3 vs. 20.0%, p=0.004), with a significantly higher level of systolic pressure [137 (120, 160) mmHg vs. 130 (120, 140) mmHg, p=0.009]. Main laboratory findings, including serial albumin (20.4±7.8 g/L vs. 24.5±6.7 g/L, p<0.001), 24-h proteinuria [5.61 (3.10, 7.87) g/day vs. 3.82 (2.31, 5.79) g/day, p=0.002], serial creatinine [80.8 (65.8, 97.9) µmol/L vs. 72.0 (58.7, 84.9) µmol/L, p=0.003], and estimated glomerular filtration rate [86 (66, 101) mL/min/1.73 m2 vs. 95 (81, 108) mL/min/1.73 m2, p=0.007] showed significant differences between the two groups. Pathologically, patients with focal segmental glomerulosclerosis lesions appeared with a higher percentage of crescents, a more severe degree of interstitial fibrosis, and a higher level of membranous nephropathy stage. Renal phospholipase A2 receptor showed a relatively lower positive rate of only 75.0% in the FSGS+ group in comparison with the positive rate of 90.3% in the FSGS- group (p=0.031). The prognosis was generally similar between the two groups. Among patients who were given non-immunosuppression treatment, those with focal segmental glomerulosclerosis lesions took a relatively longer period of time to achieve complete remission (29.3±7.0 m vs. 15.4±8.9 m, p=0.025) and experienced a higher rate of renal function deterioration (37.5 vs. 5.4%, p=0.033) compared with the other ones. While among those receiving immunosuppression treatment, both groups received similar remission rates. CONCLUSION: Compared with FSGS- group, idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions represented more severe nephrotic syndrome and worse renal function. In view of the renal function decline during the follow-up, more aggressive treatment with the use of immunosuppressants should be considered for idiopathic membranous nephropathy patients with focal segmental glomerulosclerosis lesions.
Asunto(s)
Glomerulonefritis Membranosa , Glomeruloesclerosis Focal y Segmentaria , Inmunosupresores , Humanos , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/tratamiento farmacológico , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/fisiopatología , Femenino , Masculino , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Inmunosupresores/uso terapéutico , Biopsia , Tasa de Filtración Glomerular , Proteinuria/etiología , Receptores de Fosfolipasa A2/inmunología , Pronóstico , Resultado del Tratamiento , Riñón/patología , Riñón/fisiopatologíaRESUMEN
Combined glomerulopathy is infrequent in pediatric patients. Its presence should be suspected in those patients with glomerulophaties with atypical course. The influence on the long-term renal impairment remains uncertain. Here we report two children with histological findings of combined glomerulopathy.
La combinación de glomerulopatías es infrecuente en la población pediátrica. Su presencia debe ser sospechada en aquellos pacientes con una enfermedad glomerular de curso clínico atípico. La influencia a largo plazo sobre el deterioro funcional renal permanece incierta. Se presentan dos niños con características histológicas de glomerulopatía combinada.
Asunto(s)
Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis Membranosa/diagnóstico , Preescolar , Femenino , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis Membranosa/fisiopatología , Humanos , MasculinoRESUMEN
Background: Membranous nephropathy (MN) is one of the causes of nephrotic syndrome in adults that lead to end-stage renal disease with an unknown molecular signature. The current diagnosis is based on renal biopsy, which is an invasive method and has several complications and challenges. Thus, identification of the novel biomarker candidates, as well as impaired pathways, will be helpful for non-invasive molecular-based diagnosis. Objectives: We aimed to study the molecular signature of MN and facilitate the systematic discovery of diagnostic candidate biomarkers, molecular pathway, and potential therapeutic targets using bioinformatics predictions. Methods: The protein-protein interaction (PPI) network of an integrated list of downloaded microarray data, differential proteins from a published proteomic study, and a list of retrieved scientific literature mining was constructed and analyzed in terms of functional modules, enriched biological pathways, hub genes, master regulator, and target genes. Results: These network analyses revealed several functional modules and hub genes including Vitamin D3 receptor, retinoic acid receptor RXR-alpha, interleukin 8, and SH3GL2. TEAD4 and FOXA1 were identified as the regulatory master molecules. LRP1 and ITGA3 were identified as the important target genes. Extracellular matrix organization, cell surface receptor signaling pathway, and defense and inflammatory response were found to be impaired in MN using functional analyses. A specific subnetwork for MN was suggested using PPI approach. Discussion: Omics data integration and systems biology analysis on the level of interaction networks provide a powerful approach for identification of pathway-specific biomarkers for MN.
Asunto(s)
Biología Computacional/métodos , Glomerulonefritis Membranosa/diagnóstico , Mapas de Interacción de Proteínas , Proteómica/métodos , Biomarcadores/metabolismo , Simulación por Computador , Glomerulonefritis Membranosa/fisiopatología , Humanos , Mapeo de Interacción de ProteínasRESUMEN
During the last decade, several major breakthroughs have led to the identification of human podocyte membrane antigens. Experimental involving antipodocyte antibodies in human membranous nephropathy (MN) have opened a new line of thinking about this disease, relating as an autoimmune kidney disease. In this setting, the M-type phospholipase A2 receptor (PLA2R) was identified as the first major antigen target in human primary MN. Studies have demonstrated anti-PLA2R antibodies against PLA2R ranging from 70 to 89% in patients with MN, but not in those with secondary MN. It has been suggested that the serum level of anti-PLA2R could be used for the diagnosis of idiopathic MN and for the monitoring of response to treatment. However, the coexistence of autoantibodies suggests a complex pathogenic pathway that involves different podocyte targets. New experimental models are needed to elucidate the appearance time and the role of each anti-podocyte antibody in MN development and progression.
Asunto(s)
Glomerulonefritis Membranosa/fisiopatología , Glomerulonefritis Membranosa/terapia , Animales , HumanosRESUMEN
Avanços dos conhecimentos moleculares na última década têm permitido a identificação de proteínas podocitárias que atuariam como alvos antigênicos na glomerulonefrite membranosa (GNM). Estudos envolvendo anticorpos contra estruturas podocitárias tem promovido o conceito autoimune da forma idiopática desta glomerulopatia. Neste contexto, o receptor de fosfolipase A2 do tipo M (PLA2R) tem merecido destaque como o primeiro e mais importante autoantígeno descrito na GNM idiopática humana. A presença do anticorpo anti-PLA2R tem sido destacada entre 70% e 89% de portadores da GNM idiopática, diferenciando das formas secundárias. Diversos estudos têm sugerido a detecção do anti-PLA2R como diagnóstico e apontado a correlação de seus níveis circulantes com a atividade clínica e resposta terapêutica. Entretanto, a coexistência de outros autoanticorpos sugere uma complexa via patogênica envolvendo diferentes antígenos podocitários. Estudos adicionais são necessários para esclarecer o tempo de aparecimento e o papel de cada anticorpo antipodócito no diagnóstico e progressão da GNM.
During the last decade, several major breakthroughs have led to the identification of human podocyte membrane antigens. Experimental involving antipodocyte antibodies in human membranous nephropathy (MN) have opened a new line of thinking about this disease, relating as an autoimmune kidney disease. In this setting, the M-type phospholipase A2 receptor (PLA2R) was identified as the first major antigen target in human primary MN. Studies have demonstrated anti-PLA2R antibodies against PLA2R ranging from 70 to 89% in patients with MN, but not in those with secondary MN. It has been suggested that the serum level of anti-PLA2R could be used for the diagnosis of idiopathic MN and for the monitoring of response to treatment. However, the coexistence of autoantibodies suggests a complex pathogenic pathway that involves different podocyte targets. New experimental models are needed to elucidate the appearance time and the role of each anti-podocyte antibody in MN development and progression.
Asunto(s)
Animales , Humanos , Glomerulonefritis Membranosa/fisiopatología , Glomerulonefritis Membranosa/terapiaRESUMEN
Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The J-RBR/J-KDR registry developed by the Japanese Society of Nephrology provides nationwide cohort data for epidemiological studies of MN. MN was present in 36.8% of 1,203 primary nephrotic syndrome patients in Japan. In addition, 633 (77.9%) out of 813 MN patients were referred to as "idiopathic," whereas 22.1% were classified as "secondary" and involved conditions such as systemic lupus erythematosus, drug exposure, infections, cancer, and various collagen diseases. The mean age of the MN patients was 62.2 (2-88) years old, their mean eGFR was 76.7 (7.6-154.6) ml/min/1.73 m(2), and 63.3% had hypertension at the time of renal biopsy. On the basis of these findings, half of Japanese idiopathic MN patients have risk factors (age >60, male, or lower eGFR) for end-stage renal failure, and 10% belong to the high-risk group (daily proteinuria of over 8.0 g). Further studies with high-grade evidence should resolve the natural history and therapeutic problems of idiopathic MN in elderly Japanese.
Asunto(s)
Glomerulonefritis Membranosa/epidemiología , Glomerulonefritis Membranosa/patología , Riñón/patología , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Brasil/epidemiología , Niño , Preescolar , Femenino , Tasa de Filtración Glomerular/fisiología , Glomerulonefritis Membranosa/fisiopatología , Humanos , Japón/epidemiología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/epidemiología , Síndrome Nefrótico/patología , Síndrome Nefrótico/fisiopatología , República de Corea/epidemiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Immune complex (IC) deposition in renal tissue is considered as a possible tumor marker. This raised the hypothesis that some tumor markers might be related to the patient prognosis, with emphasis in the possibility to detect them in tissue sample, not only in blood. We report a patient with membranous glomerulonephritis (MGN) and tumoral IC deposition that were detected previous to the diagnosis of melanoma. CASE REPORT: A 55-year-old male was admitted to our department with symptoms of renal disease; a kidney biopsy was performed and the diagnosis was phase II MGN. A few months later he returned to the hospital with ascites, dyspnea, anorexia, and macular erythematous skin lesions in the body. A new urinalysis showed proteinuria, hematuria, and leukocyturia; the chest X-ray showed a lung nodule; and a brain CT scan revealed a frontal nodular lesion, suggesting metastasis. The brain biopsy suggested the diagnosis of metastatic melanoma and a posterior kidney immunohistochemistry study with S-100 and HMB-45 antibodies showed glomerular and tubular positivity for these markers. CONCLUSIONS: MGN and deposition of tumoral IC as a first manifestation of melanoma has not been previously reported. This case reinforces the importance of a clinical evolution focused on the diagnosis of a hidden cancer in patients with MGN. Oncologists should also be aware of the potential occurrence of glomerular lesion in their patients and that could be important during tumor therapy.
Asunto(s)
Complejo Antígeno-Anticuerpo/metabolismo , Glomerulonefritis Membranosa/etiología , Glomérulos Renales/metabolismo , Melanoma/diagnóstico , Anticuerpos Antineoplásicos/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/secundario , Resultado Fatal , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/fisiopatología , Humanos , Inmunohistoquímica , Riñón/metabolismo , Masculino , Melanoma/complicaciones , Melanoma/metabolismo , Antígenos Específicos del Melanoma/metabolismo , Persona de Mediana Edad , Proteínas S100/metabolismoRESUMEN
La segunda parte de este trabajo tiene como objetivo principal, reafirmar conceptos vertidos en la primera parte yanalizar la fisiopatologia de algunas nefropatias que se originan en las alteraciones de la barrera de filtración glomerular (BFG). Si bien el podocito (P) ha ocupado el centro de la BFG,recientes estudios ontogenicos han demostrado que el endotelioglomerular tiene una función y estructura únicas en relación al resto del sistema endotelial del organismo,posee poros, en vez de fenestras y diafragmas; por lo tanto, es necesario, tener una visión mas integrada de la BFG. En el endotelio se han hallado dos factores de crecimiento: la angiopoietina 1 y 2 que son antagónicas e intervienenactivamente en algunas afecciones glomerulares. Someramente hemos analizado aspectos del ciclo celularmencionando algunas proteínas reguladoras en sentido positivo o negativo: las ciclinas y las kinasas respectivamente. Ante una agresión pueden responder positivamentey mantener la integridad de la BFG o desembocar en diversos tipos de nefropatias. El sistema renina angiotensina se expresa en los podocitosy, en el endotelio, sus efectos son bastante conocidos pero aun no se sabe como actúan a nivel de la BFG. La nefropatia diabética (ND) fue considerada hace años como patología mesangial primaria y los borramientos de los foot procesess (FP) como secundarios a la proteinuria; sin embargo, en la actualidad, ha sido ampliamente reconocido el hecho de que la principal causa radica en los podocitos y su proteína la nefrina. En cuanto a la nefropatia membranosa MN se ha sugerido que la patogenia radica en una activación de los podocitospor la fracción del complemeto C5b-9.Los sindromes nefróticos cortico resistentes (SNCR) son causados por mutaciones recesivas del gen NPHS2 (podocina). En niños las mutaciones del gen MPHS1 expresan la nefrina, además de la podocina, laminina B2... (AU)
The main objective of this second part of the ¶Glomerular Filtration Barrier (GFB)÷ review is to highlight some concepts previously defined in the first part of this issue and to analyze current concepts regarding the pathophysiologyof some glomerular diseases derived from alterations in this barrier. Although the podocyte always dominated the focus of our attention, recent evidences derived from ontogenic analysis of the endothelial barrier encouraged us to build up an integrated vision of the GFB. It is widely recognized that the endothelial layer has unique features like those related to structural and functional characteristics ¹like thepresence of fenestrae and diaphragm- that are distinctive. Two endothelial-derived growth factors (angiotoietin1 and 2) have antagonistic functions and are believed to have a role in some glomerular diseases. We have already mentioned that some regulatory proteins,such as cyclines and proteases, are able to react to different stimuli by retaining the integrity of the GFB or otherwise inducing glomerular injury. Podocytes and endotelial cells also express components of the renin-angiotensin-system; whose effects on the GFBare incompletely recognized. The renal involvement in diabetes mellitus was considered until recently as a primary mesangial condition with the effacement of the foot processes as a consequence of the increased urine protein excretion. Nonetheless it has been amply recognized the involvement of the podocyteborne protein, nephrine. C5b-9-complement associated podocyte activation has been considered as responsible for the development ofmembranous nephropathy. Similarly, steroid-resistant nephrotic syndrome, in children was associated with autosomic recessive genes mutations encoding different proteins with deficit of nephrin,podocyn, laminin B-2, phospholipase C-e.; and in adult patients alteration of ACTN4 as well as in the TRPC6 calcium... (AU)
Asunto(s)
Humanos , Tasa de Filtración Glomerular , Enfermedades Renales/fisiopatología , Glomerulonefritis Membranosa/fisiopatología , Nefropatías Diabéticas/fisiopatología , Glomeruloesclerosis Focal y Segmentaria/fisiopatologíaRESUMEN
La segunda parte de este trabajo tiene como objetivo principal, reafirmar conceptos vertidos en la primera parte yanalizar la fisiopatologia de algunas nefropatias que se originan en las alteraciones de la barrera de filtración glomerular (BFG). Si bien el podocito (P) ha ocupado el centro de la BFG,recientes estudios ontogenicos han demostrado que el endotelioglomerular tiene una función y estructura únicas en relación al resto del sistema endotelial del organismo,posee poros, en vez de fenestras y diafragmas; por lo tanto, es necesario, tener una visión mas integrada de la BFG. En el endotelio se han hallado dos factores de crecimiento: la angiopoietina 1 y 2 que son antagónicas e intervienenactivamente en algunas afecciones glomerulares. Someramente hemos analizado aspectos del ciclo celularmencionando algunas proteínas reguladoras en sentido positivo o negativo: las ciclinas y las kinasas respectivamente. Ante una agresión pueden responder positivamentey mantener la integridad de la BFG o desembocar en diversos tipos de nefropatias. El sistema renina angiotensina se expresa en los podocitosy, en el endotelio, sus efectos son bastante conocidos pero aun no se sabe como actúan a nivel de la BFG. La nefropatia diabética (ND) fue considerada hace años como patología mesangial primaria y los borramientos de los foot procesess (FP) como secundarios a la proteinuria; sin embargo, en la actualidad, ha sido ampliamente reconocido el hecho de que la principal causa radica en los podocitos y su proteína la nefrina. En cuanto a la nefropatia membranosa MN se ha sugerido que la patogenia radica en una activación de los podocitospor la fracción del complemeto C5b-9.Los sindromes nefróticos cortico resistentes (SNCR) son causados por mutaciones recesivas del gen NPHS2 (podocina). En niños las mutaciones del gen MPHS1 expresan la nefrina, además de la podocina, laminina B2...
The main objective of this second part of the Glomerular Filtration Barrier (GFB) review is to highlight some concepts previously defined in the first part of this issue and to analyze current concepts regarding the pathophysiologyof some glomerular diseases derived from alterations in this barrier. Although the podocyte always dominated the focus of our attention, recent evidences derived from ontogenic analysis of the endothelial barrier encouraged us to build up an integrated vision of the GFB. It is widely recognized that the endothelial layer has unique features like those related to structural and functional characteristics like thepresence of fenestrae and diaphragm- that are distinctive. Two endothelial-derived growth factors (angiotoietin1 and 2) have antagonistic functions and are believed to have a role in some glomerular diseases. We have already mentioned that some regulatory proteins,such as cyclines and proteases, are able to react to different stimuli by retaining the integrity of the GFB or otherwise inducing glomerular injury. Podocytes and endotelial cells also express components of the renin-angiotensin-system; whose effects on the GFBare incompletely recognized. The renal involvement in diabetes mellitus was considered until recently as a primary mesangial condition with the effacement of the foot processes as a consequence of the increased urine protein excretion. Nonetheless it has been amply recognized the involvement of the podocyteborne protein, nephrine. C5b-9-complement associated podocyte activation has been considered as responsible for the development ofmembranous nephropathy. Similarly, steroid-resistant nephrotic syndrome, in children was associated with autosomic recessive genes mutations encoding different proteins with deficit of nephrin,podocyn, laminin B-2, phospholipase C-e.; and in adult patients alteration of ACTN4 as well as in the TRPC6 calcium...
Asunto(s)
Humanos , Enfermedades Renales/fisiopatología , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Glomerulonefritis Membranosa/fisiopatología , Nefropatías Diabéticas/fisiopatologíaRESUMEN
Renal interstitial fibrosis has been observed in a large number of nephropathies and contributes to the progressive deterioration of renal function. Myofibroblasts have been implicated in the reparative process of tissue injury, including renal scarring secondary to glomerular diseases. We performed a retrospective study on 28 patients with biopsy-proven primary membranous nephropathy, to determine whether interstitial myofibroblasts and tubulointerstitial lesions correlated with renal function at follow-up. Tubulointerstitial pathology was evaluated by morphometric and semiquantitative methods. Interstitial myofibroblasts were counted; 24-hour urinary protein and serum creatinine at the time of diagnosis and at the end of follow-up were available for all the patients. There were 20 males and 8 females, age 2-67 years (mean 42.3+/-15.3), most of them with nephrotic syndrome (78.6%). The final renal function had deteriorated in 16 patients (57.1%) and in 5 patients (17.8%) reached end-stage. The renal outcome was correlated with histological changes. We found a positive correlation between the severity of tubulointerstitial damage and the deterioration of the final serum creatinine (r2=0.185; p=0.016). Myofibroblasts did not predict impaired renal function at the final follow-up. The current data do not support previous suggestions that myofibroblasts are a useful a predictor of end-stage renal disease.
Asunto(s)
Fibroblastos/fisiología , Glomerulonefritis Membranosa/patología , Fallo Renal Crónico/etiología , Túbulos Renales/patología , Mioblastos/fisiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Fibrosis , Estudios de Seguimiento , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury. METHODS: Renal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by alpha-smooth muscle actin (alpha-SMA) staining. RESULTS: ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in alpha-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-beta and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-beta; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation. CONCLUSION: Intrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.
Asunto(s)
Angiotensina II/metabolismo , Fibroblastos , Glomerulonefritis Membranosa/fisiopatología , Riñón/metabolismo , Miocitos del Músculo Liso , Becaplermina , Fibroblastos/patología , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Humanos , Miocitos del Músculo Liso/patología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-sis , Sistema Renina-Angiotensina , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia ArribaRESUMEN
A broad spectrum of renal changes is observed in patients with sickle cell anemia, and ideal therapeutic measures for the management of these alterations are still being studied. Affected patients have deficient urinary concentration and potassium excretion. Perhaps owing to a compensatory mechanism, the proximal tubules are in a condition of "hyperfunction", with increased sodium and phosphorus reabsorption and greater creatinine and uric acid secretion. Mild tubular acidosis may be present. No treatment has been reported for these tubular changes, except for care in the maintenance of hydration. The use of anti-inflammatory drugs is being studied in order to inhibit the prostaglandins involved in the process. Increased renal blood flow, glomerular filtration rate, and filtration fraction are frequent findings. Hematuria commonly occurs as a consequence of red blood cell sickling in the renal medulla, papillary necrosis, or even renal medullary carcinoma. Measures such as increased fluid ingestion, urine alkalinization and, if necessary, administration of epsilon-aminocaproic acid and certain invasive procedures have been proposed to treat hematuria. Nephropathy in patients with sickle cell anemia can be manifested by proteinuria and, more rarely, nephrotic syndrome. Drugs such as prednisone and cyclophosphamide are ineffective for the treatment of patients with nephrotic syndrome. Angiotensin converting enzyme inhibitors decrease proteinuria, but their long-term effect in preventing the progression of glomerular disease has not been established. Chronic renal failure, although infrequent, may be one of the manifestations of this disease. Hemodialysis and transplantation are satisfactory therapeutic options for patients with end-stage renal disease.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Enfermedades Renales/terapia , Anemia de Células Falciformes/terapia , Niño , Glomerulonefritis Membranosa/etiología , Glomerulonefritis Membranosa/fisiopatología , Glomerulonefritis Membranosa/terapia , Hematuria/etiología , Hematuria/fisiopatología , Hematuria/terapia , Hemodinámica , Humanos , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Trasplante de Riñón , Resultado del TratamientoRESUMEN
BACKGROUND: Nuclear factor-kappaB (NF-kappaB) and activated protein-1 (AP-1) are transcription factors that regulate many genes involved in the progression of renal disease. Recent data have shown that NF-kappaB is activated in tubules and glomeruli in various experimental models of renal injury. In vitro studies also suggest that proteinuria could be an important NF-kappaB activator. We therefore approached the idea that NF-kappaB may be an indicator of renal damage progression. METHODS: Paraffin-embedded renal biopsy specimens from 34 patients with intense proteinuria [14 with minimal change disease (MCD) and 20 with idiopathic membranous nephropathy (MN)] and from 7 patients with minimal or no proteinuria (IgA nephropathy) were studied by Southwestern histochemistry for the in situ detection of activated transcription factors NF-kappaB and AP-1. In addition, by immunohistochemistry, we performed staining for the NF-kappaB subunits (p50 and p65) and AP-1 subunits (c-fos, c-jun). By immunohistochemistry and/or in situ hybridization, the expression of some chemokines [monocyte chemoattractant protein-1 (MCP-1), RANTES, osteopontin (OPN)] and profibrogenic cytokines [transforming growth factor-beta (TGF-beta)], whose genes are regulated by NF-kappaB and/or AP-1, were studied further. RESULTS: NF-kappaB was detected mainly in the tubules of proteinuric patients, but rarely in nonproteinuric IgA nephropathy (IgAN) patients. In addition, there was a significant relationship between the intensity of proteinuria and NF-kappaB activation in MCD (r = 0.64, P = 0.01) and MN patients (r = 0.64, P < 0.01). Unexpectedly, patients with MCD had a significantly higher NF-kappaB tubular activation than those with MN (P < 0.01). To assess whether there was a different composition of NF-kappaB protein components, immunostaining was performed for the NF-kappaB subunits p50 and p65. However, no differences were noted between MCD and MN patients. In those patients, there was a lower tubular activation of AP-1 compared with NF-kappaB. Moreover, a strong correlation in the expression of both transcription factors was observed only in MN (r = 0.7, P = 0.004). Patients with progressive MN had an overexpression of MCP-1, RANTES, OPN, and TGF-beta, mainly in the proximal tubules, while no significant expression was found in MCD patients. CONCLUSIONS: On the whole, our results show that a tubular overactivation of NF-kappaB and AP-1 and a simultaneous up-regulation of certain proinflammatory and profibrogenic genes are markers of progressive renal disease in humans. Increased activation of solely NF-kappaB and/or AP-1 may merely indicate the response of tubular renal cells to injury.
Asunto(s)
Glomerulonefritis Membranosa/fisiopatología , Túbulos Renales/metabolismo , FN-kappa B/fisiología , Nefrosis Lipoidea/fisiopatología , Factor de Transcripción AP-1/fisiología , Adolescente , Adulto , Quimiocinas/metabolismo , Niño , Preescolar , Femenino , Glomerulonefritis Membranosa/orina , Histocitoquímica , Humanos , Inmunohistoquímica , Hibridación in Situ , Mediadores de Inflamación/metabolismo , Masculino , Nefrosis Lipoidea/orina , Proteinuria/etiología , Valores de ReferenciaRESUMEN
Nos anos 80, Brenner e colaboradores demonstraram uma associacao estreita entre anomalias da hemodinamica glomerular, especialmente a hipertensao intracapilar, e o desenvolvimento de esclerose glomerular em varios modelos de lesao cronica. Essa relacao e analoga a conhecida associacao entre hipertensao sistemica e macrovasculopatias. Varios mecanismos, tais como a proliferacao celular, a lesao endotelial e a microtrombose intracapilar, podem ligar a hipertensao intracapilar ao processo de esclerose glomerular, estimulando por exemplo a proliferacao de celulas mesangiais e a producao de matriz mesangial. Futuros estudos sobre a interacao entre eventos mecanicos e celulares devem contribuir para a elucidacao desse complexo processo
Asunto(s)
Humanos , Glomerulonefritis Membranosa/fisiopatología , Insuficiencia Renal/fisiopatología , Hipertensión Renal/fisiopatología , Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Enfermedad CrónicaRESUMEN
Os autores apresentam uma apreciaçäo clínico-patológica das glomerulonefrites na infância, relatando sua experiência no HUPE-UERJ). 1) GN com lesäo mínima: 128 casos (54,7% pré-escolares e 67,9% do sexo masculino): com prognóstico muito bom. 2) Esclerose focal e segmentar: 37 casos, quatro em remissäo, 11 com SN em atividade, 16 evoluíram para IRC (sete óbitos) e seis näo foram acompanhados. 3) GN membranosa: 10 casos, quatro em remissäo, quatro com SN em atividade e dois foram perdidos do acompanhamento. 4) GN endoteliomesangial: 257 casos, todos evoluíram para cura embora 15,3% apresentassem complicaçöes graves. 5) GN mesangial: oito casos, dois em remissäo, três com SBN em atividade, um em IRC e dois óbitos. 6) GN crescêntica: 11 pacientes, sete estäo bem, um em IRC e três morreram. 7) GN membranoproliferativa: seis pacientes: um em remissäo, dois em IRC, dois com SN em atividade e um faleceu
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Glomerulonefritis/clasificación , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Nefrosis Lipoidea/fisiopatología , Biopsia , Glomerulonefritis por IGA/patología , Glomerulonefritis Membranoproliferativa/complicaciones , Glomerulonefritis Membranosa/fisiopatología , Glomerulonefritis/patología , Nefrosis Lipoidea/complicaciones , Nefrosis Lipoidea/tratamiento farmacológico , Tromboangitis ObliteranteRESUMEN
Familial idiopathic membranous nephropathy, an immune-complex-associated glomerulopathy, has not been previously reported in father and son, despite its striking immunogenetic correlation, especially with HLA-DR3. As a dysfunction of the monocyte-phagocyte system (MPS), it has been observed linked to DR3 antigen, so we studied the MPS Fc receptor function in a father and his son with a histologically proven membranous nephropathy, associated with the haplotype A9-B35-DR3-DQw2. The Fc receptor function of the MPS was examined by measuring the clearance of IgG-sensitized, 51Cr-labeled erythrocytes and by measuring the ability of isolated monocytes to ingest autologous red blood cells coated with IgG anti-Rh (D) antibody. Immune clearance and in vitro phagocytosis was normal in both patients and not related to their levels of immune complexes (as measured by ELISA C1q and Conglutinin solid-phase binding assay). This report suggest that genetic factors may play an important role in the development of membranous nephropathy, and it seems not to be related to a dysfunction of MPS as measured by these tests.
Asunto(s)
Glomerulonefritis Membranosa/inmunología , Antígeno HLA-DR3/inmunología , Monocitos/ultraestructura , Fagocitos/ultraestructura , Receptores Fc/fisiología , Adolescente , Adulto , Complejo Antígeno-Anticuerpo/sangre , Ensayo de Inmunoadsorción Enzimática , Glomerulonefritis Membranosa/sangre , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/fisiopatología , Humanos , Masculino , Monocitos/fisiología , Fagocitos/fisiología , Fagocitosis/fisiologíaRESUMEN
Membranous glomerulonephritis and the nephrotic syndrome concurrent with the Miller-Fisher variant of the Landry-Guillain-Barré-Strohl syndrome (LGBS), acute post-infective polyneuritis, is reported in a 49-year-old man. The onset of heavy proteinuria coincided with the development of the neurological disturbance. While immunosuppressive therapy appeared to hasten improvement in the neurological disease, no such improvement occurred in the glomerulopathy.
Asunto(s)
Glomerulonefritis Membranosa/etiología , Síndrome Nefrótico/etiología , Polineuropatías/etiología , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/patología , Síndrome Nefrótico/fisiopatología , Polineuropatías/patología , Polineuropatías/fisiopatologíaRESUMEN
Membranous glomerulonephritis and the nephrotic syndrome concurrent with the Miller-Fisher variant of the Landry-Guillain-Barre-Strohl syndrome (LGBS), acute post-infective polyneuritis, is reported in a 49-year-old man. The onset of heavy proteinuria coincided with the development of the neurological disturbance. While immunosuppressive therapy appeared to hasten improvement in the neurological disease, no such improvement occurred in the glomerulopathy (AU)
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Glomerulonefritis Membranosa/etiología , Síndrome Nefrótico/etiología , Neuritas/etiología , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/fisiopatología , Síndrome Nefrótico/patología , Síndrome Nefrótico/fisiopatología , Neuritas/patología , Neuritas/fisiopatología , BarbadosRESUMEN
Membranous glomerulonephritis and the nephrotic syndrome concurrent with the Miller-Fisher variant of the Landry-Guillain-Barré-Strohl syndrome (LGBS), acute post-infective polyneuritis, is reported in a 49-year-old man. The onset of heavy proteinuria coincided with the development of the neurological disturbance. While immunosuppressive therapy appeared to hasten improvemente in the neurological disease, no such improvemente occurred in the glomerulopathy