RESUMEN
We present an unusual case of metastatic renal cell carcinoma (RCC) mimicking diverticulitis in a 76-year-old man with a 16-year history of chronic lymphocytic leukaemia (CLL) and a 2â cm left renal mass. The patient presented with severe abdominal pain and lower gastrointestinal bleeding with anticoagulation from recent pulmonary embolism. His clinical course was troubled by recurrent hospitalisations and complications that delayed investigations and potential treatments. Radiographic findings revealed stable CLL, mild sigmoid diverticulitis and a small renal mass. Small renal masses (less than 4â cm) are considered low risk for metastasising and are, thus, often observed or ablated, rather than resected. Furthermore, gastrointestinal metastases from RCC are rare. This case adds new perspective to the unpredictable nature of RCC and how synchronous malignancies may be masked in patients with long-standing CLL.
Asunto(s)
Carcinoma de Células Renales/secundario , Diverticulitis/diagnóstico , Hemorragia Gastrointestinal/etiología , Neoplasias Renales/patología , Leucemia Linfocítica Crónica de Células B/complicaciones , Enfermedades del Sigmoide/diagnóstico , Dolor Abdominal/etiología , Anciano , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/diagnóstico , Diagnóstico Diferencial , Resultado Fatal , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/diagnóstico , Masculino , Enfermedades del Sigmoide/etiologíaRESUMEN
Kidney allografts are frequently lost due to alloimmunity. Still, the impact of early acute rejection (AR) on long-term graft survival is debated. We examined this relationship focusing on graft histology post-AR and assessing specific causes of graft loss. Included are 797 recipients without anti-donor antibodies (DSA) at transplant who had 1 year protocol biopsies. 15.2% of recipients had AR diagnosed by protocol or clinical biopsies. Compared to no-AR, all histologic types of AR led to abnormal histology in 1 and 2 years protocol biopsies, including more fibrosis + inflammation (6.3% vs. 21.9%), moderate/severe fibrosis (7.7% vs. 13.5%) and transplant glomerulopathy (1.4% vs. 8.3%, all p < 0.0001). AR were associated with reduced graft survival (HR = 3.07 (1.92-4.94), p < 0.0001). However, only those AR episodes followed by abnormal histology led to reduced graft survival. Early AR related to more late alloimmune-mediated graft losses, particularly transplant glomerulopathy (31% of losses). Related to this outcome, recipients with AR were more likely to have new DSA class II 1 year posttransplant (no-AR, 11.1%; AR, 21.2%, p = 0.039). In DSA negative recipients, early AR often leads to persistent graft inflammation and increases the risk of new DSA II production. Both of these post-AR events are associated with increased risk of graft loss.
Asunto(s)
Aloinjertos , Biopsia , Rechazo de Injerto/patología , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Adulto , Anciano , Aloinjertos/patología , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Humanos , Riñón/inmunología , Riñón/patología , Riñón/fisiología , Enfermedades Renales , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Donantes de TejidosRESUMEN
We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post-transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria.
Asunto(s)
Glomerulonefritis Membranosa/etiología , Glomerulonefritis Membranosa/patología , Enfermedades Renales/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Glomerulonefritis Membranosa/tratamiento farmacológico , Humanos , Factores Inmunológicos/uso terapéutico , Enfermedades Renales/complicaciones , Masculino , Persona de Mediana Edad , Pronóstico , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Proteinuria/patología , Recurrencia , Estudios Retrospectivos , Rituximab , Trasplante HomólogoRESUMEN
We assessed the relationship between living donor (LD) age and kidney survival in 1063 adults transplanted between 1980 and 2007. Increasing LD age was associated with lower kidney function (GFR) before and after transplantation and loss of GFR beyond 1 year. Increasing LD age was also associated with low-moderate proteinuria posttransplant (151-1500 mg/day, p < 0.0001). By univariate analysis, reduced graft survival related to lower GFR at 1 year [HR = 0.925 (0.906-0.944), p < 0.0001], proteinuria [HR = 1.481 (1.333-1.646), p < 0.0001] and increasing LD age [HR = 1.271 (1.219-1.326), p = 0.001]. The impact of LD age on graft survival was noted particularly >4 years posttransplant and was modified by recipient age. Thus, compared to a kidney graft that was within 5 years of the recipient age, younger kidneys had a survival advantage [HR = 0.600 (0.380-0.949), p = 0.029] while older kidneys had a survival disadvantage [HR = 2.217 (1.507-3.261), p < 0.0001]. However, this effect was seen only in recipients <50 years old. By multivariate analysis, the relationship between LD age and graft survival was independent of GFR but related to proteinuria. In conclusion, LD age is an important determinant of long-term graft survival, particularly in younger recipients. Older kidneys with reduced survival are identifiable by the development of proteinuria posttransplant.
Asunto(s)
Factores de Edad , Trasplante de Riñón , Donadores Vivos , Resultado del Tratamiento , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The objective of this study was to determine the impact of lupus nephritis disease activity on maternal and foetal outcomes in pregnant patients with systemic lupus erythematosus (SLE). Medical records of all pregnant patients with SLE treated at our institution between 1976 and 2007 were reviewed. All patients met American College of Rheumatology classification criteria for SLE. Demographic data, history of lupus nephritis, nephritis disease activity and maternal and foetal outcomes of pregnancy were abstracted. Active lupus nephritis was defined as the presence of proteinuria >0.5 g/day and/or active urinary sediment with or without an elevation in serum creatinine (Cr). Quiescent lupus nephritis was confirmed in the presence of proteinuria <0.5 mg/day and inactive urinary sediment. We identified 58 patients with 90 pregnancies. Compared with pregnancies in SLE patients without renal involvement (n = 47), pregnancies in patients with active lupus nephritis (n = 23) were associated with a higher incidence of maternal complications (57% vs 11%, P < 0.001), whereas those with quiescent lupus nephritis (n = 20) were not (35% vs 11%, P = 0.10). Women with active lupus nephritis were more likely to deliver preterm than women without lupus nephritis, median of 34 weeks vs 40 gestational weeks, respectively (P = 0.002) and were more likely to suffer foetal loss (35% vs 9%, P = 0.031). Active, but not quiescent, lupus nephritis during pregnancy is associated with a higher incidence of maternal and foetal complications compared with pregnancies in SLE patients without renal involvement.
Asunto(s)
Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/complicaciones , Complicaciones del Embarazo/etiología , Resultado del Embarazo , Adulto , Creatinina/sangre , Femenino , Muerte Fetal/epidemiología , Muerte Fetal/etiología , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Nefritis Lúpica/fisiopatología , Embarazo , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/etiología , Proteinuria/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. MN can recur after kidney transplantation causing proteinuria, allograft dysfunction and graft failure. In this study we assessed the incidence of MN recurrence utilizing surveillance graft biopsies. The study included 1310 renal allograft recipients from 2000 to 2006. Glomerular diseases were the cause of kidney failure in 28% of patients and 23 (2%) had idiopathic MN. Recurrent MN was diagnosed in eight of 19 patients included in this analysis (42%) 13 +/- 20 months (median = 4; range 2-61 months) after transplant. The initial clinical manifestations of recurrent MN were mild or absent. Urine protein excretion was 825 +/- 959 (64-2286) mg/day and three patients had no proteinuria. Five of seven patients who did not receive additional immunosuppression for MN had significant increases in proteinuria during follow up and three became nephrotic. At diagnosis, light microscopic changes were subtle or absent. All patients had granular glomerular basement membrane deposits of IgG but little or absent C3 by immunofluorescence. Subepithelial deposits were observed in all cases by electron microscopy. In conclusion, idiopathic MN recurred in 42% of patients after transplantation. The initial clinical and histologic manifestations are subtle but the disease is progressive.
Asunto(s)
Glomerulonefritis Membranosa/patología , Trasplante de Riñón/efectos adversos , Riñón/patología , Adulto , Anciano , Biopsia , Femenino , Glomerulonefritis Membranosa/epidemiología , Glomerulonefritis Membranosa/etiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
Vascular access dysfunction contributes to patient morbidity during maintenance hemodialysis. In this study we determined if knockout of heme oxygenase-1 predisposed to malfunction of arteriovenous fistulas. After three weeks, all fistulas in wild type mice were patent whereas a third of the fistulas in knockout mice were occluded and these exhibited increased neointimal hyperplasia and venous wall thickening. Heme oxygenase-1 mRNA and protein were robustly induced in the fistulas of the wild type mice. In the knockout mice there was increased PAI-1 and MCP-1 expression, marked induction of MMP-2 and MMP-9, but similar expression of PDGF alpha, IGF-1, TGF-beta1, VEGF, and osteopontin compared to wild type mice. We conclude that heme oxygenase-1 deficiency promotes vasculopathic gene expression, accelerates neointimal hyperplasia and impairs the function of arteriovenous fistulas.
Asunto(s)
Catéteres de Permanencia/efectos adversos , Hemo-Oxigenasa 1/deficiencia , Animales , Derivación Arteriovenosa Quirúrgica , Vasos Sanguíneos/lesiones , Vasos Sanguíneos/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/fisiología , Ratones , Ratones Noqueados , Túnica Íntima/patologíaRESUMEN
Heme oxygenase-1 may exert cytoprotective effects. In this study we examined the sensitivity of heme oxygenase-1 knockout (HO-1(-/-)) mice to renal ischemia by assessing glomerular filtration rate (GFR) and cytokine expression in the kidney, and inflammatory responses in the systemic circulation and in vital extrarenal organs. Four hours after renal ischemia, the GFR of HO-1(-/-) mice was much lower than that of wild-type mice in the absence of changes in renal blood flow or cardiac output. Eight hours after renal ischemia, there was a marked induction of interleukin-6 (IL-6) mRNA and its downstream signaling effector, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), in the kidney, lung, and heart in HO-1(-/-) mice. Systemic levels of IL-6 were markedly and uniquely increased in HO-1(-/-) mice after ischemia as compared to wild-type mice. The administration of an antibody to IL-6 protected against the renal dysfunction and mortality observed in HO-1(-/-) mice following ischemia. We suggest that the exaggerated production of IL-6, occurring regionally and systemically following localized renal ischemia, in an HO-1-deficient state may underlie the heightened sensitivity observed in this setting.
Asunto(s)
Tasa de Filtración Glomerular/fisiología , Hemo-Oxigenasa 1/metabolismo , Isquemia/fisiopatología , Riñón/irrigación sanguínea , Animales , Gasto Cardíaco/fisiología , Citocinas/sangre , Femenino , Hemo-Oxigenasa 1/genética , Interleucina-6/metabolismo , Isquemia/metabolismo , Riñón/metabolismo , Riñón/fisiopatología , Pulmón/metabolismo , Masculino , Ratones , Ratones Noqueados , Miocardio/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Flujo Sanguíneo Regional/fisiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatología , Factor de Transcripción STAT3/metabolismo , Factores de TiempoRESUMEN
OBJECTIVES: Pristane-induced lupus is a well-established model of murine lupus. Mice injected with Pristane develop lupus-specific autoantibodies and glomerulonephritis. A chance observation led us to identify and characterize haemorrhagic pulmonary capillaritis in Pristane-injected mice. METHODS: Eight-week-old C57Bl/10 (B10, H-2(b)) mice received a single intraperitoneal injection of 0.5 ml of Pristane. Control mice received phosphate-buffered saline (PBS) injection. Mice were bled at 2 weeks after Pristane injection and monthly thereafter for serology and for antinuclear antibody (ANA). To characterize pulmonary disease, bronchoalveolar lavage (BAL) was carried out for total and differential cell count. Cytokines levels were checked for IL-2, IL-4, TNF-alpha, IFN-gamma, IL-6 and IL-10. Lungs were examined by histopathology and electron microscopy. RESULTS: All mice injected with Pristane developed a pulmonary capillaritis with perivascular infiltration with macrophages, neutrophils, lymphocytes and eosinophils. In addition, alveoli showed macrophage and neutrophil infiltration. The degree of perivascular and alveolar inflammation was moderate to severe. BAL was inflammatory with cell composition of macrophages, neutrophils, lymphocyte and eosinophils. There was evidence of endothelial injury on electron microscopy but no evidence of immune complex deposition. IL-6 and IL-10 were increased in BAL but levels of TNF-alpha, IFN-gamma, IL-2 and IL-4 were not. Anti-neutrophil cytoplasm antibody (ANCA) was negative. Kidneys demonstrated an increase in mesangial matrix and cellularity compatible with WHO Class II lupus lesion. There were immune complexes and complement deposition in the kidney. There were oil granulomas in peritoneum, spleen and liver but no evidence of vasculitis in these organs was seen. CONCLUSION: The relative ease and high penetrability of lesion makes it an attractive model to study pulmonary vasculitis.
Asunto(s)
Hemorragia/inducido químicamente , Enfermedades Pulmonares/inducido químicamente , Lupus Eritematoso Sistémico/inducido químicamente , Terpenos/toxicidad , Vasculitis/inducido químicamente , Animales , Anticuerpos Antinucleares/biosíntesis , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Granuloma de Cuerpo Extraño/inducido químicamente , Granuloma de Cuerpo Extraño/patología , Hemorragia/inmunología , Hemorragia/patología , Inmunosupresores/toxicidad , Interleucina-10/biosíntesis , Interleucina-6/biosíntesis , Pulmón/ultraestructura , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Endogámicos C57BL , Vasculitis/inmunología , Vasculitis/patologíaRESUMEN
Rituximab, intravenous immunoglobulin (IVIG) and rabbit antithymocyte globulin (rATG) all have been suggested to have an effect on antibody producing cells, however, supporting data are lacking. To assess the impact of these agents on splenic B-cell populations in vivo, we retrospectively examined 25 spleens removed from patients treated with these agents as part of desensitization protocols in either ABO incompatible or positive crossmatch living donor kidney transplantation. These were compared to control (CTL) spleens removed for trauma. CTLs and spleens removed at transplant after multiple pretransplant plasmaphereses (PP) plus low-dose IVIG showed similar large numbers of naïve B cells (CD20+ and CD79+), plasma cells (CD138+) and memory B cells (CD27+ cells). Adding rituximab to this PP/IVIG regimen reduced the number naïve B cells, but had no effect on memory or plasma cells. Combination treatment (PP/IVIG, rituximab and rATG) showed a trend toward the reduction of CD27+ cells, but again plasma cells were unchanged. We conclude that none of these protocols reduces splenic plasma cells in vivo. PP/low-dose IVIG does not alter splenic B cells, but the addition of rituximab decreases mature B cells. Memory B cells may be affected by combination therapy including rATG and requires further study.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Desensibilización Inmunológica/métodos , Bazo/patología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales de Origen Murino , Antígenos CD20/metabolismo , Suero Antilinfocítico/farmacología , Subgrupos de Linfocitos B/efectos de los fármacos , Antígenos CD79/metabolismo , Humanos , Inmunoglobulinas Intravenosas/farmacología , Factores Inmunológicos/farmacología , Células Plasmáticas/inmunología , Células Plasmáticas/patología , Plasmaféresis/métodos , Conejos , Estudios Retrospectivos , Rituximab , Bazo/efectos de los fármacos , Bazo/inmunología , Sindecano-1/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
The link between obesity and renal disease is unclear, and there is no consensus as to whether obese individuals are at increased risk for kidney disease after living kidney donation if they otherwise meet acceptance criteria. We retrospectively studied time-zero (implantation) biopsies in 49 obese (body mass index (BMI) > or = 30 kg/m2) and 41 non-obese (BMI < 30 kg/m2) renal donors that met acceptance criteria. We found that our obese donor population had higher systolic blood pressure (P < 0.001 vs non-obese) and higher absolute iothalamate clearance (P = 0.001 vs non-obese) before donation. The obese donors had larger glomerular planar surface area compared to non-obese controls (P = 0.017), and this parameter correlated with patient weight and urinary microalbumin excretion. Detailed examination of the biopsies revealed that although most histologic findings were similar between groups, the obese donors had more tubular dilation (P = 0.01), but less tubular vacuolization (P = 0.02) than the non-obese controls. There was also a trend toward more arterial hyalinosis in the obese patients than controls (P = 0.08). From these data, our studies detected subtle differences in donor organs obtained from obese compared to non-obese individuals. Further studies should be carried out to quantify the long-term impact of these findings.
Asunto(s)
Glomérulos Renales/citología , Glomérulos Renales/patología , Donadores Vivos , Obesidad/patología , Adulto , Anciano , Biopsia , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular/fisiología , Humanos , Glomérulos Renales/fisiología , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Nefrectomía/efectos adversos , Obesidad/fisiopatología , Tamaño de los Órganos , Complicaciones Posoperatorias/prevención & control , Estudios RetrospectivosRESUMEN
Recent protocols have allowed successful positive crossmatch (+XM) and ABO incompatible (ABOI) kidney transplantation, although their long-term outcome is not clear. To begin to assess this issue we compared protocol biopsies performed 12 months posttransplant in 37 +XM, 24 ABOI and 198 conventional allografts. Although the majority in all three groups had only minimal histologic changes, transplant glomerulopathy (TG) was significantly increased in +XM (22% vs. 13% ABOI vs. 8% conventional, p = 0.015), and correlated with prior humoral rejection (HR) by multivariate analysis (odds ratio 17.5, p < or = 0.0001). Patients with a prior history of HR also had a significant increase in interstitial fibrosis (No HR 54% vs. HR 86%, p = 0.045). In the absence of HR no difference in histologic changes was seen between groups, although all three groups had a demonstrable mild increase in interstitial fibrosis from biopsies performed at the time of transplant. Thus, although HR is associated with an increase in TG, in its absence allograft histology is similar in +XM, ABOI and conventional allografts 1 year posttransplant.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/inmunología , Incompatibilidad de Grupos Sanguíneos/inmunología , Incompatibilidad de Grupos Sanguíneos/patología , Trasplante de Riñón/inmunología , Trasplante de Riñón/patología , Donadores Vivos , Sistema del Grupo Sanguíneo ABO/metabolismo , Biopsia , Incompatibilidad de Grupos Sanguíneos/metabolismo , Complemento C4/metabolismo , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
OBJECTIVE: The role of high fat diets in breast cancer/mammary tumor (MT) development is controversial. This may be partially attributable to variable effects of high fat diets on body weight. Here, we used a moderately high fat diet (32.5% fat calories) expected to cause obesity in most mice, but predicted to result in some mice remaining in the weight range of mice fed the low fat diet (11% fat calories). This provided the opportunity to compare mice fed the high fat diet exhibiting different body weights and mice of similar weight consuming high vs low fat diets. EXPERIMENTAL METHODS: Transgenic MMTV-TGF-alpha mice, a model of postmenopausal breast cancer, consumed a low fat diet, that is, chow-fed (n=25) or a moderately high fat diet from 10 weeks of age (n=51). Body weight at 34 weeks of age was used to assign high fat diet mice to obesity-prone>overweight>obesity-resistant groups (n=17) (P<0.0001). Mice were euthanized when MTs developed or at 85 weeks of age. RESULTS: Final body weights were highest in obesity-prone>overweight >obesity-resistant=chow-fed mice. Fat pads and fat pad:carcass were heaviest in obesity-prone followed by overweight mice. However, obesity-resistant mice had fat pad weights and fat pad:carcass three-fold greater than chow-fed mice. All groups had MT incidences between 72 and 82%. Obesity-prone mice exhibited the shortest MT latency (P<0.0001), but obesity-resistant mice had significantly shorter latency than chow-fed mice. CONCLUSIONS: Consumption of a high fat diet increased adiposity and shortened MT latency in relation to its effect on body weight. These results indicate a complex role of dietary fat level on mammary tumorigenesis.
Asunto(s)
Peso Corporal , Grasas de la Dieta/administración & dosificación , Neoplasias Mamarias Experimentales/patología , Animales , Femenino , Virus del Tumor Mamario del Ratón , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
PHEX, a phosphate-regulating gene with homologies to endopeptidases on the X chromosome, is mutated in X-linked hypophosphatemia (XLH) in humans and mice (Hyp). Although recent observations indicate that Phex protein is expressed primarily in bone and may play an important role in osteoblast function and bone mineralization, the pattern of the Phex protein expression in the developing skeleton and its subcellular localization in osteoblasts remain unknown. We examined the ontogeny of the Phex protein in the developing mouse embryo and its subcellular localization in osteoblasts using a specific antibody to the protein. Immunohistochemical staining of mouse embryos revealed expression of Phex in osteogenic precursors in developing vertebral bodies and developing long bones on day 16 postcoitum (pc) and thereafter. Calvaria from day 18 pc mice showed Phex epitopes in osteoblasts. No Phex immunoreactivity was detected in lung, heart, hepatocytes, kidney, intestine, skeletal muscle, or adipose tissue of mouse embryos. Interestingly, embryonic mouse skin showed moderate amounts of Phex immunostaining. In postnatal mice, Phex expression was observed in osteoblasts and osteocytes. Moderate expression of Phex was seen in odontoblasts and slight immunoreactivity was observed in ameloblasts. Confocal microscopy revealed the presence of immunoreactive PHEX protein in the Golgi apparatus and endoplasmic reticulum of osteoblasts from normal mice and in osteoblasts from Hyp mice transduced with a human PHEX viral expression vector. PHEX protein was not detected in untransduced Hyp osteoblasts. These data indicate that Phex protein is expressed in osteoblasts and osteocytes during the embryonic and postnatal periods and that within bone, Phex may be a unique marker for cells of the osteoblast/osteocyte lineage.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Osteoblastos/metabolismo , Proteínas/metabolismo , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Retículo Endoplásmico/metabolismo , Femenino , Aparato de Golgi/metabolismo , Placa de Crecimiento/metabolismo , Humanos , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/fisiopatología , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Endopeptidasa Neutra Reguladora de Fosfato PHEX , Proteínas/genética , Proteínas/inmunología , Piel/embriología , Piel/metabolismo , Cráneo/embriología , Cráneo/metabolismoRESUMEN
IgA nephropathy (IgAN) is now recognized as the most common primary glomerulonephritis worldwide. Although the clinical course is variable, many patients develop slowly progressive renal disease, culminating in end-stage renal disease 10-20 years after diagnosis. Some recent randomized clinical trials have suggested that dietary fish oil supplementation may be a relatively safe long-term therapeutic option for preventing the development of progressive renal disease in patients with IgAN. However, other studies have failed to demonstrate a protective effect of dietary fish oil supplementation in treatment of IgAN. Although in vitro studies have provided a theoretical basis for the use of dietary fish oil supplementation, potential mechanisms underlying the protective effect of fish oil have not been well defined. In this overview, recent clinical and experimental data providing a basis for the use of dietary fish oil supplementation in treatment of IgAN and other progressive renal diseases are reviewed.
Asunto(s)
Suplementos Dietéticos , Aceites de Pescado/uso terapéutico , Glomerulonefritis por IGA/prevención & control , Animales , Ensayos Clínicos como Asunto , Humanos , RatasRESUMEN
BACKGROUND: It is widely held that liver disease predisposes toward acute tubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to glycerol-induced acute tubular necrosis in the rat. METHODS: Acute cholestatic liver disease was induced by ligation of the common bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. Renal injury was assessed by plasma creatinine concentration and renal histology. An in vitro model of heme protein-induced renal injury (hemoglobin in conjunction with glutathione depletion) was employed to assess the cytoprotective effects of bilirubin. RESULTS: Ligation of the common bile duct markedly reduced acute renal injury that occurs in the glycerol model (7.5 mL/kg body weight), as evidenced by a lower plasma creatinine concentration and less severe renal histologic injury. At a higher dose of glycerol (10 mL/kg body weight), ligation of the common bile duct again reduced renal injury and cumulative mortality that occurs five days after the induction of this model of acute renal failure. These protective effects of ligation of the common bile duct could not be ascribed to less severe muscle injury or red cell damage. Ligation of the common bile duct induced heme oxygenase-1 in the kidney and markedly so in the liver. Inhibition of heme oxygenase significantly attenuated, but did not prevent, the protective effects conferred by ligation of the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective against heme protein-induced cell injury in vitro. CONCLUSIONS: Ligation of the common bile duct confers resistance to glycerol-induced acute tubular necrosis in the rat, actions that arise, in part, from the induction of heme oxygenase-1 in the kidney and liver. Bilirubin, in micromolar concentrations, protects against heme protein-induced renal injury. Our studies uncover a novel form of acquired resistance to renal injury, occurring, unexpectedly, in the setting of acute cholestatic liver disease. We speculate that such potentially cytoprotective alterations may safeguard the kidney against irreversible functional and structural injury in the hepatorenal syndrome.
Asunto(s)
Lesión Renal Aguda/prevención & control , Colestasis Intrahepática/fisiopatología , Síndrome Hepatorrenal/fisiopatología , Lesión Renal Aguda/etiología , Animales , Colestasis Intrahepática/sangre , Creatinina/sangre , Modelos Animales de Enfermedad , Glicerol , Hemo Oxigenasa (Desciclizante)/biosíntesis , Hemo-Oxigenasa 1 , Necrosis Tubular Aguda/complicaciones , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
IEX-1 is an immediate early gene that is induced by ionizing radiation, ultraviolet radiation, and a variety of growth factors. It plays an important role in the regulation of cellular growth. Earlier, we performed studies on the distribution of IEX-1 messenger RNA in different tissues and on the subcellular localization of IEX-1 protein. No reports, however, have appeared concerning the distribution of IEX-1 protein in a variety of human tissues. We raised a polyclonal antibody against a synthetic IEX-1 peptide (amino acids 51-75) and used the antibody to study the distribution of the protein in human tissues. We demonstrate that IEX-1 is strongly expressed in epithelia of the skin, trachea, gastrointestinal, and genitourinary systems, as well as in the pancreas and breast. Endothelial cells within the vasculature of most tissue/organs also strongly express IEX-1. Liver, lung, lymph nodes, and placenta stain weakly. No IEX-1 epitopes were detected in the thymus, testes, ovary, myocardium, skeletal muscle, or spleen. We conclude that IEX-1 is widely expressed in epithelial and endocrine tissues, as well as in vascular endothelium.
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Proteínas Inmediatas-Precoces/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Proteínas de Neoplasias , Secuencia de Aminoácidos , Proteínas Reguladoras de la Apoptosis , Sistema Digestivo/metabolismo , Femenino , Humanos , Tejido Linfoide/metabolismo , Masculino , Proteínas de la Membrana , Datos de Secuencia Molecular , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Sistema Nervioso/metabolismo , Próstata/metabolismo , Sistema Respiratorio/metabolismo , Piel/metabolismo , Piel/patología , Distribución Tisular , Sistema Urogenital/metabolismo , Útero/metabolismoRESUMEN
BACKGROUND: The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation. Methods and Results-- Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (tau) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*P<0.05 versus controls: 139+/-4* versus 123+/-4 mm Hg), week 5 (174+/-7* versus 124+/-4 mm Hg), and week 12 (181+/-12* versus 124+/-4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. tau was increased in HTN-5wk (50+/-3* ms) and HTN-12wk (62+/-10* ms) dogs compared with sham (41+/-2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls. CONCLUSIONS: Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.
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Hipertensión/patología , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Angiotensina II/sangre , Animales , Catecolaminas/sangre , Diástole/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Endotelina-1/sangre , Ventrículos Cardíacos/patología , Hemodinámica , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/patología , Riñón/fisiopatología , Péptido Natriurético Encefálico/sangre , Propranolol/farmacología , Renina/sangre , Sístole/efectos de los fármacos , Disfunción Ventricular Izquierda/etiologíaRESUMEN
Signaling via release of Ca2+ from intracellular stores is mediated by several systems, including the inositol 1,4,5-trisphosphate (IP3) and cADP-ribose (cADPR) pathway. We recently discovered a high capacity for cADPR synthesis in rat glomeruli and cultured mesangial cells (MC). We sought to determine whether 1) cADPR synthesis in MC is regulated by cytokines and hormones, 2) ryanodine receptors (RyRs) are expressed in MC, and 3) Ca2+ is released through RyRs in response to cADPR. We found that ADP-ribosyl cyclase, a CD38-like enzyme that catalyzes cADPR synthesis, is upregulated in MC by tumor necrosis factor-alpha, interleukin-1beta, and all-trans retinoic acid (atRA). [3H]ryanodine binds to microsomal fractions from MC with high affinity in a Ca2+-dependent manner; binding is enhanced by specific RyR agonists and blocked by ruthenium red and cADPR. Western blot analysis confirmed the presence of RyR in MC. Release of 45Ca2+ from MC microsomes was stimulated by cADPR; release was blocked by ruthenium red and 8-bromo-cADPR. ADPR (non-cyclic) was without effect. In MC, TNF-alpha and atRA amplified the increment of cytoplasmic Ca2+ elicited by vasopressin. We conclude that MC possess elements of a novel ADP-ribosyl cyclase-->cADPR-->RyR-->Ca2+-release signaling pathway subject to regulation by proinflammatory cytokines and steroid superfamily hormones.
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Adenosina Difosfato Ribosa/farmacología , Antígenos CD , Calcio/metabolismo , Mesangio Glomerular/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Adenosina Difosfato Ribosa/análogos & derivados , Animales , Antígenos de Diferenciación/metabolismo , Cationes Bivalentes , Células Cultivadas , ADP-Ribosa Cíclica , Mesangio Glomerular/efectos de los fármacos , Interleucina-1/farmacología , Lipopolisacáridos/farmacología , Masculino , Glicoproteínas de Membrana , NAD+ Nucleosidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Tretinoina/farmacología , Triyodotironina/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba , Vasopresinas/farmacologíaRESUMEN
Chronic nephropathy is a recognized complication of sickle cell disease. Using a transgenic sickle mouse, we examined whether oxidative stress occurs in the sickle kidney, the origins and functional significance of such oxidant stress, and the expression of the oxidant-inducible, potentially protective gene, heme oxygenase-1 (HO-1); we also examined the expression of HO-1 in the kidney and in circulating endothelial cells in sickle patients. We demonstrate that this transgenic sickle mouse exhibits renal enlargement, medullary congestion, and a reduced plasma creatinine concentration. Oxidative stress is present in the kidney as indicated by increased amounts of lipid peroxidation; heme content is markedly increased in the kidney. Exacerbation of oxidative stress by inhibiting glutathione synthesis with buthionine-sulfoximine dramatically increased red blood cell sickling in the sickle kidney: in buthionine-sulfoximine-treated sickle mice, red blood cell sickling extended from the medulla into the cortical capillaries and glomeruli. HO activity is increased in the sickle mouse kidney, and is due to induction of HO-1. In the human sickle kidney, HO-1 is induced in renal tubules, interstitial cells, and in the vasculature. Expression of HO-1 is increased in circulating endothelial cells in patients with sickle cell disease. These results provide the novel demonstration that oxidative stress occurs in the sickle kidney, and that acute exacerbation of oxidative stress in the sickle mouse precipitates acute vaso-occlusive disease. Additionally, the oxidant-inducible, heme-degrading enzyme, HO-1, is induced regionally in the murine and human sickle kidney, and systemically, in circulating endothelial cells in sickle patients.