RESUMEN
The relationship between cellular senescence and fibrosis in the kidney is being elucidated and we have identified it as therapeutic target in recent studies. Chronic kidney disease has also become a lifestyle disease, often developing on the background of hypertension and dyslipidemia. In this study, we clarify the effect of interaction between these two conditions on kidney fibrosis and senescence. Wild type mice (WT), apolipoprotein E-/- mice (ApoEKO), and endothelial nitric oxide synthase (eNOS)-/- ApoE-/- mice (DKO) were obtained by breeding. Unilateral ureteral obstruction (UUO) was performed on 8-10 week old male mice and the degree of renal tubular injury, fibrosis and kidney senescence were evaluated. DKO manifested elevated blood pressure, higher total cholesterol and lower HDL than WT. DKO showed sustained kidney injury molecule-1 protein expression. Kidney fibrosis was significantly higher in ApoEKO and DKO. mRNA expression of genes related to kidney fibrosis was the highest in DKO. The mRNA expression of Zinc-α2-Glycoprotein and heme oxygenase-1 were significantly decreased in DKO. Furthermore, mRNA expression of p53, p21 and p16 were increased both in ApoEKO and DKO, with DKO being the highest. Senescence associated ß-gal positive tubule area was significantly increased in DKO. Increased DNA damage and target of rapamycin-autophagy spatial coupling compartments (TASCCs) formation was found in DKO. Mice with endothelial dysfunction and dyslipidemia developed kidney fibrosis and accelerated senescence even in young mice after injury. These data highlight the fact managing lifestyle-related diseases from a young age is important for CKD prevention.
Asunto(s)
Apolipoproteínas E/deficiencia , Senescencia Celular/genética , Fibrosis/genética , Eliminación de Gen , Riñón/patología , Óxido Nítrico Sintasa de Tipo III/deficiencia , Insuficiencia Renal Crónica/genética , Animales , Apolipoproteínas E/genética , Autofagia , Presión Sanguínea , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Daño del ADN/genética , Genes p16 , Genes p53 , Humanos , Riñón/lesiones , Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: When we encounter patients who present with both a neck mass and nephrotic syndrome, both malignancy and Kimura's disease need to be evaluated as the therapeutic strategies differ vastly between them. CASE PRESENTATION: We present the case of a 27-year-old male patient with neck mass and nephrotic syndrome. The presence of both eosinophilia and elevated immunoglobulin E levels were concerning for Kimura's disease, which is an allergic syndrome defined by eosinophilic granulomas of neck soft tissue along with peripheral eosinophilia. The eventual final diagnosis, however, was sclerosing mucoepidermoid carcinoma of parotid gland with both eosinophilia and membranous nephropathy. Following the surgical resection of the mass, the nephrotic syndrome completely resolved. CONCLUSION: Detailed histopathological assessments of both the parotid gland and renal tissue were key aspects of the diagnosis and management to exclude Kimura's disease.
Asunto(s)
Carcinoma Mucoepidermoide/diagnóstico , Eosinofilia/sangre , Glomerulonefritis Membranosa/diagnóstico , Inmunoglobulina E/sangre , Enfermedad de Kimura/diagnóstico , Neoplasias de la Parótida/diagnóstico , Adulto , Carcinoma Mucoepidermoide/complicaciones , Carcinoma Mucoepidermoide/patología , Carcinoma Mucoepidermoide/cirugía , Diagnóstico Diferencial , Eosinofilia/complicaciones , Glomerulonefritis Membranosa/etiología , Glomerulonefritis Membranosa/patología , Humanos , Masculino , Neoplasias de la Parótida/complicaciones , Neoplasias de la Parótida/patología , Neoplasias de la Parótida/cirugíaRESUMEN
Diabetic nephropathy (DN) causes mesangial matrix expansion, which results in glomerulosclerosis and renal failure. Collagen IV (COL4) is a major component of the mesangial matrix that is positively regulated by bone morphogenetic protein 4 (BMP4)/suppressor of mothers against decapentaplegic (Smad1) signaling. Because previous studies showed that retinoids treatment had a beneficial effect on kidney disease, we investigated the therapeutic potential of retinoids in DN, focusing especially on the regulatory mechanism of BMP4. Diabetes was induced with streptozotocin in 12-wk-old male Crl:CD1(ICR) mice, and, 1 mo later, we initiated intraperitoneal injection of all-trans retinoic acid (ATRA) three times weekly. Glomerular matrix expansion, which was associated with increased BMP4, phosphorylated Smad1, and COL4 expression, worsened in diabetic mice at 24 wk of age. ATRA administration alleviated DN and downregulated BMP4, phosopho-Smad1, and COL4. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor-α (RARα) agonist significantly decreased BMP4 and COL4 expression. Genomic analysis suggested two putative retinoic acid response elements (RAREs) for the mouse Bmp4 gene. Chromatin immunoprecipitation analysis and reporter assays indicated a putative RARE of the Bmp4 gene, located 11,488-11,501 bp upstream of exon 1A and bound to RARα and retinoid X receptor (RXR), which suppressed BMP4 expression after ATRA addition. ATRA suppressed BMP4 via binding of a RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice. These findings provide a novel regulatory mechanism for treatment of DN.
Asunto(s)
Proteína Morfogenética Ósea 4/efectos de los fármacos , Colágeno Tipo IV/efectos de los fármacos , Nefropatías Diabéticas/metabolismo , Células Mesangiales/efectos de los fármacos , Tretinoina/farmacología , Animales , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Células Cultivadas , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Células Mesangiales/metabolismo , Ratones , Elementos de Respuesta , Receptor alfa de Ácido Retinoico/agonistas , Receptores X Retinoide/metabolismo , Proteína Smad1/efectos de los fármacos , Proteína Smad1/genética , Proteína Smad1/metabolismoRESUMEN
The glomerulus is a network of capillaries known as a tuft, located at the beginning of a nephron in the kidney. Here we describe a novel method for the induction of a macroscopically visible three-dimensional glomerulus-like sphere (GLS). This procedure did not require any additional cytokines and completed the formation of spheres within 24â¯h. After the formation was complete, GLS maintained a steady state for at least five days without proliferation and without a decrease in viability. Therefore, this procedure assists various assays for a prolong period of time. Overall, our protocol allows for a very simple mixing of cells from different sources to obtain fine-grained and highly dispersed GLSs. The kidney filtration barrier is a unique structure characterized by a complex three-dimensional framework of podocytes and endothelial cells. GLS exhibited the induction of many podocyte-specific gene profiles similar to those in adult human kidneys, suggesting that the sphere formation process is important for the maturation of podocytes. Focal segmental glomerulosclerosis (FSGS) is one of the major causes of steroid-resistant nephrotic syndrome, and some circulating permeability factors in the patient's serum FSGS have been implicated in the pathogenesis of the disease. Serum from patients with FSGS induced the collapse of GLS, which imitates the appearance of glomerulosclerosis in patients. In conclusion, the investigation and use of GLS may provide a novel method to elucidate the molecular mechanisms underlying complicated and unexplained events in glomeruli in a similar condition in adult kidneys.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomérulos Renales/metabolismo , Células Cultivadas , Glomeruloesclerosis Focal y Segmentaria/sangre , HumanosRESUMEN
BACKGROUND: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. METHODS: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. RESULTS: Low eGFR (<60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤-50% change and -50 to -30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio. CONCLUSION: These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.
Asunto(s)
Albuminuria/fisiopatología , Diabetes Mellitus Tipo 2/epidemiología , Nefropatías Diabéticas/fisiopatología , Tasa de Filtración Glomerular , Fallo Renal Crónico/fisiopatología , Riñón/fisiopatología , Anciano , Albuminuria/diagnóstico , Albuminuria/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Incidencia , Japón/epidemiología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/epidemiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Factores de TiempoRESUMEN
Human glomerular diseases can be caused by several different diseases, many of which include mesangial expansion and/or proliferation followed by glomerulosclerosis. However, molecular mechanisms underlying the pathologic mesangial changes remain poorly understood. Here, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1)-S6 kinase pathway in mesangial expansion and/or proliferation by ablating an upstream negative regulator, tuberous sclerosis complex 1 (TSC1), using tamoxifen-induced Foxd1-Cre mice [Foxd1ER(+) TSC1 mice]. Foxd1ER(+) TSC1 mice showed mesangial expansion with increased production of collagen IV, collagen I, and α-smooth muscle actin in glomeruli, but did not exhibit significant mesangial proliferation or albuminuria. Furthermore, rapamycin treatment of Foxd1ER(+) TSC1 mice suppressed mesangial expansion. Among biopsy specimens from patients with glomerular diseases, analysis of phosphorylated ribosomal protein S6 revealed mesangial cell mTORC1 activation in IgA nephropathy and in lupus mesangial proliferative nephritis but not in the early phase of diabetic nephropathy. In summary, mesangial cell mTORC1 activation can cause mesangial expansion and has clinical relevance for human glomerular diseases. This report also confirms that the tamoxifen-induced mesangium-specific Cre-loxP system is useful for studies designed to clarify the role of the mesangium in glomerular diseases in adults.
Asunto(s)
Enfermedades Renales/enzimología , Células Mesangiales/enzimología , Complejos Multiproteicos/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Femenino , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones TransgénicosRESUMEN
BACKGROUND: Immunoglobulin G4-related kidney disease characterized by immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis has distinctive serological and radiological findings. Renal prognosis is good because of a good response to glucocorticoids. Here we report a case of successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure. CASE PRESENTATION: A 59-year-old Japanese man was referred to our hospital because of uremia with a creatinine level of 12.36 mg/dL. Urinalysis revealed mild proteinuria and hyperß2microglobulinuria, and blood tests showed hyperglobulinemia with an IgG level of 3243 mg/dL and an IgG4 level of 621 mg/dL. Non-contrast computed tomography revealed renal mass-like regions. Based on the findings, immunoglobulin G4-related kidney disease was suspected, however, further radiological examination showed unexpected results. Ga-67 scintigraphy showed no kidney uptake. T2-weighted magnetic resonance imaging revealed high-intensity signals which corresponded to mass-like regions and multiple patchy low-intensity signals in kidney cortex. Finally, the patient was diagnosed with immunoglobulin G4-related kidney disease by renal pathology of severe immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis and characteristic fibrosis. He received 50 mg oral prednisolone, which was tapered with a subsequent decrease of serum creatinine and IgG4 levels. One year after initiation of treatment, he achieved normalization of serum IgG4 level and proteinuria, and remained off dialysis with a creatinine level of 3.50 mg/dL. After treatment with steroids, repeat imaging suggested bilateral severe focal atrophy. However, mass-like regions did not show atrophic change although renal atrophy was evident in patchy low-intensity lesions on T2-weighted magnetic resonance imaging. These findings suggest that multiple patchy low-intensity signals and high-intensity mass-like regions were mildly atrophic lesions of immunoglobulin G4-related kidney disease due to severe fibrosis and normal parts of kidney, respectively. CONCLUSIONS: In immunoglobulin G4-related kidney disease with severe kidney failure, radiological findings should be carefully examined. In addition, renal prognosis may be good despite highly advanced tubulointerstitial nephritis and fibrosis.
Asunto(s)
Inmunoglobulina G/metabolismo , Fallo Renal Crónico/diagnóstico por imagen , Fallo Renal Crónico/metabolismo , Nefritis Intersticial/diagnóstico por imagen , Nefritis Intersticial/metabolismo , Antiinflamatorios/uso terapéutico , Humanos , Inmunoglobulina G/análisis , Fallo Renal Crónico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Nefritis Intersticial/tratamiento farmacológico , Prednisolona/uso terapéutico , Resultado del TratamientoRESUMEN
Prepump arterial pressure (PreAP) is monitored to avoid generating excessive negative pressure. The National Kidney Foundation K/DOQI clinical practice guidelines for vascular access recommend that PreAP should not fall below -250 mm Hg because excessive negative PreAP can lead to a decrease in the delivery of blood flow, inadequate dialysis, and hemolysis. Nonetheless, these recommendations are consistently disregarded in clinical practice and pressure sensors are often removed from the dialysis circuit. Thus far, delivered blood flow has been reported to decrease at values more negative than -150 mm Hg of PreAP. These values have been analyzed by an ultrasonic flowmeter and not directly measured. Furthermore, no known group has evaluated whether PreAP-induced hemolysis occurs at a particular threshold. Therefore, the aim of this study was to clarify the importance of PreAP in the prediction of inadequate dialysis and hemolysis. By using different diameter needles, human blood samples from healthy volunteers were circulated in a closed dialysis circuit. The relationship between PreAP and delivered blood flow or PreAP and hemolysis was investigated. We also investigated the optimal value for PreAP using several empirical monitoring methods, such as a pressure pillow. Our investigation indicated that PreAP is a critical factor in the determination of delivered blood flow and hemolysis, both of which occured at pressure values more negative than -150 mm Hg. With the exception of direct pressure monitoring, commonly used monitoring methods for PreAP were determined to be ineffective. We propose that the use of a vacuum monitor would permit regular measurement of PreAP.
Asunto(s)
Hemólisis , Monitoreo Fisiológico , Diálisis Renal , Adulto , Anciano , Presión Arterial , Velocidad del Flujo Sanguíneo , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Diálisis Renal/efectos adversos , Diálisis Renal/instrumentación , Diálisis Renal/métodosRESUMEN
BACKGROUND: The aim of this study is to examine the outcomes of an accelerated fractionated irradiation for N0 glottic carcinoma. METHODS: In this retrospective analysis, 29 patients with N0 glottic carcinoma treated by radiation therapy were enrolled. Thirteen patients had T1a disease, six had T1b disease, and ten had T2 disease. A fractional dose of 2.1 Gy was administered to seven patients. The total doses were 65.1 and 67.2 Gy in four and three patients, respectively. A fractional dose of 2.25 Gy was administered to 22 patients. The total doses were 63 and 67.5 Gy in 21 patients and 1 patient with T2 disease, respectively. Additionally, 13 patients underwent the use of TS-1 (80-100 mg per day). RESULTS: The median follow-up period was 33 months, and the 3-year local control rate was 95.6%. No patient had a lymph node or distant recurrence. As acute adverse events, grades 2 and 3 dermatitis were observed in 18 patients and 1 patient, and grades 2 and 3 mucositis were observed in 15 patients and 1 patient. As a late adverse event, one patient required tracheotomy because of laryngeal edema occurring. CONCLUSIONS: Accelerated fractionated irradiation may be an option in the radiation therapy of N0 glottic carcinoma because of its ability to shorten the treatment time.
Asunto(s)
Fraccionamiento de la Dosis de Radiación , Glotis , Neoplasias Laríngeas , Humanos , Masculino , Femenino , Neoplasias Laríngeas/radioterapia , Persona de Mediana Edad , Anciano , Glotis/patología , Estudios Retrospectivos , Adulto , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
Activation of mesangial cells (MCs), which is characterized by induction of smooth muscle α-actin (SMA) expression, contributes to a key event in various renal diseases; however, the mechanisms controlling MC differentiation are still largely undefined. Activated Smad1 induced SMA in a dose-dependent manner in MCs. As a direct regulating molecule for SMA, we identified and characterized scleraxis (Scx) as a new phenotype modulator in advanced glycation end product (AGE)-exposed MCs. Scx physically associated with E12 and bound the E-box in the promoter of SMA and negatively regulated the AGE-induced SMA expression. Scx induced expression and secretion of bone morphogenetic protein 4 (BMP4), thereby controlling the Smad1 activation in AGE-treated MCs. In diabetic mice, Scx was concomitantly expressed with SMA in the glomeruli. Inhibitor of differentiation 1 (Id1) was further induced by extended treatment with AGE, thereby dislodging Scx from the SMA promoter. These data suggest that Scx and Id1 are involved in the BMP4-Smad1-SMA signal transduction pathway besides the TGFß1-Smad1-SMA signaling pathway and modulate phenotypic changes in MCs in diabetic nephropathy.
Asunto(s)
Actinas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteína Morfogenética Ósea 4/biosíntesis , Nefropatías Diabéticas/metabolismo , Mesangio Glomerular/metabolismo , Transducción de Señal , Proteína Smad1/metabolismo , Actinas/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteína Morfogenética Ósea 4/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Regulación de la Expresión Génica/genética , Mesangio Glomerular/patología , Productos Finales de Glicación Avanzada/genética , Productos Finales de Glicación Avanzada/metabolismo , Proteína 1 Inhibidora de la Diferenciación/genética , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Masculino , Ratones , Elementos de Respuesta/genética , Proteína Smad1/genética , Factor de Transcripción 3/genética , Factor de Transcripción 3/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Matrix Gla protein (MGP) is one of the important proteins inhibiting vascular calcification (VC). Single nucleotide polymorphisms (SNPs) located in the promoter and coding regions of the MGP gene affect the transcriptional activity. In this study, we investigated the relationship between the SNPs and progression of VC in patients undergoing maintenance hemodialysis (MHD). METHODS: This was a retrospective, longitudinal cohort study of 134 MHD patients whose VC could be followed by multi-detector computed tomography (MDCT) examinations. MGP-SNPs (T-138C, rs1800802 and G-7A, rs1800801) were determined. The progression speed of VC was examined by plotting the abdominal aortic calcium volume scores. RESULTS: The progression speed of VC of patients with the CC genotype of T-138C was significantly slower than that of patients with the CT or TT genotype. Multiple regression analysis showed that CT/TT genotype, greater age at the beginning of MHD, male sex, high levels of calcium × phosphate, low levels of high-density lipoprotein cholesterol, high levels of low-density lipoprotein cholesterol, low levels of ferritin and non-use of angiotensin II receptor blockers were significantly associated with progression of VC. CONCLUSIONS: The MGP-138CC genotype may be associated with slower progression of VC in MHD patients. The genotype of the MGP gene will be a genomic biomarker that is predictive of VC progression.
Asunto(s)
Proteínas de Unión al Calcio/genética , Proteínas de la Matriz Extracelular/genética , Diálisis Renal/efectos adversos , Calcificación Vascular/genética , Adulto , Anciano , Aorta Abdominal/diagnóstico por imagen , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Calcificación Vascular/diagnóstico por imagen , Proteína Gla de la MatrizRESUMEN
BACKGROUND: Diabetic nephropathy, leading to end-stage renal disease, has a considerable impact on public health and the social economy. However, there are few national registries of diabetic nephropathy in Japan. The aims of this prospective cohort study are to obtain clinical data and urine samples for revising the clinical staging of diabetic nephropathy, and developing new diagnostic markers for early diabetic nephropathy. METHODS: The Japanese Society of Nephrology established a nationwide, web-based, and prospective registry system. On the system, there are two basic registries; the Japan Renal Biopsy Registry (JRBR), and the Japan Kidney Disease Registry (JKDR). In addition to the two basic registries, we established a new prospective registry to the system; the Japan Diabetic Nephropathy Cohort Study (JDNCS), which collected physical and laboratory data. RESULTS: We analyzed the data of 321 participants (106 female, 215 male; average age 65 years) in the JDNCS. Systolic and diastolic blood pressure was 130.1 and 72.3 mmHg, respectively. Median estimated glomerular filtration rate (eGFR) was 33.3 ml/min/1.73 m(2). Proteinuria was 1.8 g/gCr, and serum levels of albumin were 3.6 g/dl. The majority of the JDNCS patients presented with preserved eGFR and low albuminuria or low eGFR and advanced proteinuria. In the JRBR and JKDR registries, 484 and 125 participants, respectively, were enrolled as having diabetes mellitus. In comparison with the JRBR and JKDR registries, the JDNCS was characterized by diabetic patients presenting with low proteinuria with moderately preserved eGFR. CONCLUSIONS: There are few national registries of diabetic nephropathy to evaluate prognosis in Japan. Future analysis of the JDNCS will provide clinical insights into the epidemiology and renal and cardiovascular outcomes of type 2 diabetic patients in Japan.
Asunto(s)
Nefropatías Diabéticas/diagnóstico , Sistema de Registros , Anciano , Albuminuria/epidemiología , Biopsia , Estudios de Cohortes , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Japón/epidemiología , Riñón/patología , Enfermedades Renales/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteinuria/epidemiologíaRESUMEN
BACKGROUND: The pectoralis major musculocutaneous flap (PMMF) is a pedicled flap often used as a reconstruction option in head and neck surgery, especially in cases with poor wound healing. However, applying PMMF after esophageal surgery is uncommon. We report here, the case of a successfully repaired refractory anastomotic fistula (RF) after total esophagectomy, by PMMF. CASE PRESENTATION: A 73-year-old man had a history of hypopharyngolaryngectomy, cervical esophagectomy, and reconstruction using a free jejunal graft for hypopharyngeal carcinosarcoma at the age of 54. He also received conservative treatment for pharyngo-jejunal anastomotic leakage (AL), then postoperative radiation therapy. This time, he was diagnosed with carcinosarcoma in the upper thoracic esophagus; cT3rN0M0, cStageII, according to the Japanese Classification of Esophageal Cancer 12th Edition. As a salvage surgery, thoracoscopic total resection of the esophageal remnant and reconstruction using gastric tube via posterior mediastinal route was performed. The distal side of the jejunal graft was cut and re-anastomosed with the top of the gastric tube. An AL was observed on the 6th postoperative day (POD), and after 2 months of conservative treatment was then diagnosed as RF. The 3/4 circumference of the anterior wall of the gastric tube was ruptured for 6 cm in length, and surgical repair using PMMF was performed on POD71. The edge of the defect was exposed and the PMMF (10 × 5 cm) fed by thoracoacromial vessels was prepared. Then, the skin of the flap and the wedge of the leakage were hand sutured via double layers with the skin of the flap facing the intestinal lumen. Although a minor AL was observed on POD19, it healed with conservative treatment. No complications, such as stenosis, reflux, re-leakage, were observed over 3 years of postoperative follow-up. CONCLUSIONS: The PMMF is a useful option for repairing intractable AL after esophagectomy, especially in cases with large defect, as well as difficulties for microvascular anastomosis due to previous operation, radiation, or wound inflammation.
RESUMEN
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease. We have previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix (ECM) proteins in DN. However, little is known about the regulatory mechanisms that induce and activate Smad1. Here, bone morphogenetic protein 4 (Bmp4) was found to up-regulate the expression of Smad1 in mesangial cells and subsequently to phosphorylate Smad1 downstream of the advanced glycation end product-receptor for advanced glycation end product signaling pathway. Moreover, Bmp4 utilized Alk3 and affected the activation of Smad1 and Col4 expressions in mesangial cells. In the diabetic mouse, Bmp4 was remarkably activated in the glomeruli, and the mesangial area was expanded. To elucidate the direct function of Bmp4 action in the kidneys, we generated transgenic mice inducible for the expression of Bmp4. Tamoxifen treatment dramatically induced the expression of Bmp4, especially in the glomeruli of the mice. Notably, in the nondiabetic condition, the mice exhibited not only an expansion of the mesangial area and thickening of the basement membrane but also remarkable albuminuria, which are consistent with the distinct glomerular injuries in DN. ECM protein overexpression and activation of Smad1 in the glomeruli were also observed in the mice. The mesangial expansion in the mice was significantly correlated with albuminuria. Furthermore, the heterozygous Bmp4 knock-out mice inhibited the glomerular injuries compared with wild type mice in diabetic conditions. Here, we show that BMP4 may act as an upstream regulatory molecule for the process of ECM accumulation in DN and thereby reveals a new aspect of the molecular mechanisms involved in DN.
Asunto(s)
Proteína Morfogenética Ósea 4/biosíntesis , Nefropatías Diabéticas/metabolismo , Matriz Extracelular/metabolismo , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Células Mesangiales/metabolismo , Regulación hacia Arriba , Albuminuria/genética , Albuminuria/metabolismo , Albuminuria/patología , Animales , Proteína Morfogenética Ósea 4/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Matriz Extracelular/genética , Matriz Extracelular/patología , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Productos Finales de Glicación Avanzada/genética , Productos Finales de Glicación Avanzada/metabolismo , Células Mesangiales/patología , Ratones , Ratones Noqueados , Proteína Smad1/genética , Proteína Smad1/metabolismoRESUMEN
Diabetic nephropathy (DN) is the most important chronic kidney disease. We previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix in DN. Phenotypic change in mesangial cells (MCs) is a key pathologic event in the progression of DN. The aim of this study is to investigate a novel mechanism underlying chondrogenic phenotypic change in MCs that results in the development of DN. MCs showed chondrogenic potential in a micromass culture, and BMP4 induced the expression of chondrocyte markers (SRY-related HMG Box 9 (SOX9) and type II collagen (COL2)). Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of BMP4, hypoxia-inducible factor-1α (HIF-1α), and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of proteoglycans and COL2 in MCs. Furthermore, forced expression of Smad1 induced chondrocyte markers as well. Dorsomorphin inhibited these inductions. Glomerular expressions of HIF-1α, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. These positive stainings were observed in mesangial sclerotic lesions. SOX9 was partially colocalized with HIF-1α and BMP4 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. Here we demonstrate that HIF-1α and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.
Asunto(s)
Antígenos de Diferenciación/biosíntesis , Transdiferenciación Celular , Condrocitos/metabolismo , Nefropatías Diabéticas/metabolismo , Regulación de la Expresión Génica , Mesangio Glomerular/metabolismo , Factor de Transcripción SOX9/biosíntesis , Animales , Antígenos de Diferenciación/genética , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Línea Celular , Condrocitos/patología , Colágeno Tipo II/biosíntesis , Colágeno Tipo II/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Mesangio Glomerular/patología , Productos Finales de Glicación Avanzada/genética , Productos Finales de Glicación Avanzada/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Transgénicos , Factor de Transcripción SOX9/genética , Proteína Smad1/genética , Proteína Smad1/metabolismoRESUMEN
Anti-glomerular basement membrane (GBM) antibody disease is clinically manifested as rapidly progressive glomerulonephritis (RPGN) with crescentic changes. The renal prognosis is poor. We report here the case of a 61-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive anti-GBM antibody disease. This patient was referred to our hospital because of RPGN. Anti-GBM antibody was positive with a titer of 38 EU. The MPO-ANCA titer was 65 EU. Chest imaging examination revealed pulmonary multiple nodules. ANCA-associated vasculitis was suspected. Renal pathology revealed cellular crescents in 13 out of 17 glomeruli. Immunofluorescence with anti-IgG antibody, anti-C3 antibody, and anti-fibrin antibody showed linear staining along the glomerular capillary walls. Based on these findings, the patient was diagnosed with anti-GBM antibody disease. Hemodialysis was started because of uremic syndrome with elevated serum creatinine (6.84 mg/dL). In addition, treatment with plasma exchange using 3.6 L (90 mL/kg) of fresh frozen plasma combined with an oral dose of 40 mg of prednisolone was initiated. Within 3 weeks, both types of autoantibodies became undetectable. Subsequently, this patient achieved dialysis independence and remission of glomerulonephritis. No adverse effects were observed. In patients with MPO-ANCA-positive anti-GBM antibody disease, intensive therapy predominantly with plasma exchange might be operative, even though renal function is less likely to recover.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Autoanticuerpos/inmunología , Glomerulonefritis/inmunología , Hemorragia/inmunología , Terapia de Inmunosupresión/métodos , Enfermedades Pulmonares/inmunología , Peroxidasa/inmunología , Intercambio Plasmático/métodos , Plasmaféresis/métodos , Anticuerpos Antiidiotipos/inmunología , Biopsia , Líquido del Lavado Bronquioalveolar/citología , Broncoscopía , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Glomerulonefritis/diagnóstico , Glomerulonefritis/terapia , Hemorragia/diagnóstico , Hemorragia/terapia , Humanos , Inmunoglobulina G/inmunología , Inmunosupresores/uso terapéutico , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/terapia , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
A 50-year-old man who underwent hemodialysis (HD) at local outpatient HD center due to end-stage renal disease (ESRD) was transferred to our hospital because of pneumonia. He had severe emaciation and past history of congestive heart failure. Presenting symptoms almost consistently involved difficulty in hearing and recurrent attacks of migraine-like headaches. He was diagnosed with dilated cardiomyopathy, showing diastolic mechanical dyssynchrony by tissue Doppler echocardiography. On the day of death, he had hematemesis and hemorrhagic shock. Autopsy revealed perforation of duodenum, and genetic analysis using mitochondrial DNA from cardiac muscle and iliopsoas muscle revealed a 3243A > G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Multiple organ failure due to the mutation of mitochondrial DNA with gastrointestinal bleeding is not a common.
Asunto(s)
Acidosis Láctica/patología , Hemorragia Gastrointestinal/patología , Fallo Renal Crónico/complicaciones , Síndrome MELAS/patología , Miopatías Mitocondriales/patología , Acidosis Láctica/etiología , Autopsia , Biopsia , Diagnóstico Diferencial , Resultado Fatal , Hemorragia Gastrointestinal/etiología , Humanos , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Síndrome MELAS/etiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miopatías Mitocondriales/etiología , Diálisis RenalRESUMEN
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and a major contributor to morbidity and mortality of diabetic patients throughout the world. Albuminuria is one of the most characteristic functional changes in the early phase of DN. However, many recent studies have shown that there was no clear association between glomerulosclerosis and albuminuria in type 1 and 2 diabetes. DN is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli and is morphologically characterized by progressive expansion of mesangial matrix and thickening of the glomerular basement membrane. Type IV collagen (Col4) is a major component of the extracellular matrix (ECM) in the expanded mesangial matrix. Advanced glycation endproducts (AGEs) produced as the result of hyperglycemia are known to stimulate the production of ECM proteins in mesangial cells, resulting in glomerulosclerosis. Using a yeast one-hybrid screening, Smad1 was identified as a transcriptional regulator of Col4 in AGE-treated mesangial cells. Smad1 also regulated other ECM proteins, such as type I collagen and osteopontin, as well as alpha smooth muscle actin. Moreover, there was a very good correlation between urinary Smad1 levels and the development of mesangial expansion, whereas the correlation between albuminuria and mesangial expansion was not significant in experimental DN models. In addition, urinary Smad1 was revealed to be a good predictor for later onset of morphological changes and to be used to monitor the effect of ARB in DN. In conclusion, urinary Smad1 is expected to be a useful diagnostic biomarker for DN.
Asunto(s)
Nefropatías Diabéticas/etiología , Albuminuria/metabolismo , Animales , Biomarcadores/análisis , Colágeno Tipo IV/metabolismo , Nefropatías Diabéticas/metabolismo , Humanos , Proteína Smad1/análisis , Proteína Smad1/metabolismoRESUMEN
Arteriosclerotic renal artery stenosis is one of the increasingly common diseases that affects many aged patients. There are various non-invasive methods to diagnose renal artery stenosis, such as contrast enhanced CT or MRI. However, these methods are not appropriate for patients with renal dysfunction. Ultrasound sonography is becoming one of the promising methods to diagnose artery stenosis because of photographic improvements. In this case, a 72-year-old woman was hospitalized 7 months after nephrectomy because of severe hypertension, heart failure and kidney dysfunction. The heart failure was quite uncontrollable in spite of massive administration of diuretics, and finally, hemodialysis was started to control her volume status. In consideration of her past history and abdominal bruit, we evaluated the renal artery stenosis by ultrasound sonography and confirmed the diagnosis by renal angiography. To improve hypertension control, we performed renal artery stenting, which resulted in an impressive improvement of her blood pressure and renal function. We recognized the importance of careful causal evaluation of renal dysfunction, even though it is difficult to apply invasive therapy to patients after nephrectomy.
Asunto(s)
Hipertensión/terapia , Nefrectomía , Obstrucción de la Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/terapia , Insuficiencia Renal/terapia , Stents , Anciano , Femenino , Insuficiencia Cardíaca/etiología , Humanos , Hipertensión/etiología , Obstrucción de la Arteria Renal/complicaciones , Insuficiencia Renal/etiología , Resultado del Tratamiento , UltrasonografíaRESUMEN
Tubulointerstitial nephritis (TIN) with IgM-positive plasma cells (IgMPC-TIN) is an autoimmune kidney disease characterized by IgM/CD138-double-positive plasma cell infiltration in the tubulointerstitium. A 50-year-old man developed IgMPC-TIN and presented with crystalline inclusions in the rough endoplasmic reticulum. Intracellular crystal formation is a rare finding in paraprotein-related kidney diseases, but this case showed no pathogenic monoclonal immunoglobulin. Prednisolone (PSL, 30 mg) improved the TIN, but PSL tapering resulted in the recurrence of TIN. Combination therapy with 15 mg PSL and 150 mg mizoribine ultimately stabilized TIN. This case offers original evidence concerning the pathophysiology and treatment strategy of IgMPC-TIN.