RESUMEN
BACKGROUND: Although hepatitis C virus (HCV) infection is known to be associated with Type 2 cryoglobulinemic glomerulopathy (CG), only a few reports about other types of nephropathy have been published. METHODS: 68 HCV antibody positive patients in whom renal biopsy had been performed for persistent proteinuria, hematuria, and/or renal dysfunction between 1992 and 2008 at our institute were included. The histological, clinical and laboratory characteristics including the age, gender, hypertension, diabetes mellitus, liver histology (chronic hepatitis or liver cirrhosis), HCV-RNA, HCV genotype, splenomegaly, gastroesophageal varices, serum creatinine, hemoglobin, platelet count, rheumatoid factor, cryoglobulin, IgG, IgA, IgM, CH50, C3, C4, creatinine clearance, 24-h protein excretion, and hematuria, between their nephropathy with and without immune deposition were compared. RESULTS: Nephropathy was classified into two groups based on the detection of immune deposits by immunofluorescence microscopy: i.e., a positive group (n = 39) and a negative group (n = 29). The former group was further classified into three types of nephropathy: IgG dominant group (n = 10) (including membranous nephropathy (MN)), IgA dominant group (n = 20) (including IgA nephropathy (IgAN)), membranoproliferative glomerulonephritis (MPGN) (IgA type)), and IgM dominant group (n = 9) (MPGN apart from the IgA type). The latter group included diabetic nephropathy (n = 13), focal glomerular sclerosis (n = 4), and benign nephrosclerosis (n = 3), malignant nephrosclerosis (n = 1), tubulointerstitial nephritis (TIN) (n = 2), minimal change nephrotic syndrome (n = 1), cast nephropathy (n = 1), granulomatous TIN (n = 1), and others (n = 3). An increased serum IgM level, hypocomplementemia, splenomegaly, thrombocytopenia, liver cirrhosis, hematuria, and a high HCV RNA level were features of patients with MPGN of IgM dominant group (consistent with "CG"). CONCLUSIONS: Our results showed various histological patterns of HCV-related kidney disease and the specificity of CG, and revealed that a minority of HCV patients (n = 7) presented typical CG, while IgAN, MN, and diabetic nephropathy were more frequent.
Asunto(s)
Crioglobulinemia/patología , Hepatitis C/complicaciones , Enfermedades Renales/patología , Adulto , Anciano , Biopsia , Distribución de Chi-Cuadrado , Proteínas del Sistema Complemento/análisis , Crioglobulinemia/inmunología , Crioglobulinemia/virología , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/virología , Femenino , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/virología , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranoproliferativa/virología , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/virología , Hematuria/patología , Hematuria/virología , Hepacivirus/genética , Hepacivirus/inmunología , Hepatitis C/diagnóstico , Anticuerpos contra la Hepatitis C/sangre , Humanos , Japón , Enfermedades Renales/clasificación , Enfermedades Renales/inmunología , Enfermedades Renales/terapia , Enfermedades Renales/virología , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Nefritis Intersticial/patología , Nefritis Intersticial/virología , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/virología , Valor Predictivo de las Pruebas , Proteinuria/patología , Proteinuria/virología , ARN Viral/sangre , Diálisis Renal , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Septic shock is associated with vasopressin deficiency and hypersensitivity to its exogenous administration. The aim of this study is to review the 28-day survival rate, hemodynamic and renal effects of vasopressin therapy in refractory septic shock Japanese patients. METHODS: 55 Japanese patients experiencing catecholamine-resistant septic shock were treated with vasopressin. Hemodynamic alterations and the serum concentrations of aspartate aminotransferase, total bilirubin and creatinine clearance were evaluated following vasopressin treatment. RESULTS: In both, survivors and non-surviving patients, treatment with vasopressin resulted in a significantly increase in mean arterial pressure, hourly urine output, and a significant decrease in heart rate and total pressor dosage requirements. Creatinine clearance was significantly increased only in survivors. There were no significant changes in the serum concentrations of aspartate aminotransferase and total bilirubin. The 28-day survival rate was 45% (25 patients). CONCLUSIONS: In Japanese septic shock patients, vasopressin infusion improved hemodynamic status and reduced catecholamine requirement, and 28-day survival rate was 45%.
Asunto(s)
Dopamina/farmacología , Resistencia a Medicamentos , Infecciones por Bacterias Gramnegativas/mortalidad , Infecciones por Bacterias Grampositivas/mortalidad , Norepinefrina/farmacología , Choque Séptico/mortalidad , Vasopresinas/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Cardiotónicos/farmacología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Estudios de Seguimiento , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/fisiopatología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/fisiopatología , Humanos , Infusiones Intravenosas , Japón/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Choque Séptico/tratamiento farmacológico , Choque Séptico/fisiopatología , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del Tratamiento , Vasoconstrictores/administración & dosificaciónRESUMEN
Because pregnancy is rare in women with end-stage renal disease, dialysis patients have not been reported to present with acute abdominal symptoms related to pregnancy including ectopic pregnancy. A 41-year-old woman treated with hemodialysis for over 18 years was brought to the emergency room at our institution because of acute abdominal pain. Ultrasonography detected an abdominal fluid collection, and her anemia had worsened (hematocrit 18%). Emergency laparoscopic exploration disclosed a hemorrhagic corpus luteum of pregnancy, causing ovarian bleeding on the left. Coagulation of bleeding points was carried out. At this time, pregnancy at 7 weeks of gestation was discovered. After the procedures, hemodialysis frequency was increased to 5 times weekly, and an erythropoietin derivative was administered to maintain a hematocrit above 30%. The patient developed no hypertension. At 33 weeks of gestation, cesarean section was performed because of a decrease in amniotic fluid and frequent late deceleration of the fetal heart rate. A live baby girl weighing 1,422 g was born. The successful pregnancy reflects remarkable progress in dialysis technology. Pregnancy, then, can underlie an acute abdomen in childbearing-age women (14 - 44 years old) undergoing long-term dialysis.
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Abdomen Agudo/etiología , Cuerpo Lúteo , Hemorragia/complicaciones , Diálisis Renal , Abdomen Agudo/diagnóstico , Abdomen Agudo/cirugía , Adulto , Cesárea , Diagnóstico Diferencial , Endosonografía , Femenino , Hemorragia/diagnóstico , Hemorragia/cirugía , Humanos , Fallo Renal Crónico/terapia , Laparoscopía , Embarazo , Resultado del Embarazo , Tomografía Computarizada por Rayos XRESUMEN
Multicentric Castleman disease is a systemic lymphoproliferative disease with incomplete understood etiology. The various renal complications of this disease may include minimal change disease, mesangial proliferative glomerulonephritis, membranous glomerulonephritis and nephrotic syndrome, caused by secondary amyloidosis. In several reported cases of localized Castleman disease associated with renal amyloidosis and nephrotic syndrome, resection of organs involved by lymphoid proliferation resulted in complete remission. However, therapy of multicentric Castleman disease with renal amyloidosis is not well-established. We treated a case of a 39-year-old woman with multicentric Castleman disease complicated by nephrotic syndrome caused by secondary AA amyloidosis. The patient underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), achieving complete remission. Autologous stem cell transplantation may be an attractive choice in therapy for refractory multicentric Castleman disease.
Asunto(s)
Amiloidosis/etiología , Enfermedad de Castleman/complicaciones , Enfermedad de Castleman/terapia , Fallo Renal Crónico/etiología , Síndrome Nefrótico/etiología , Adulto , Amiloidosis/terapia , Femenino , Humanos , Fallo Renal Crónico/terapia , Melfalán/administración & dosificación , Agonistas Mieloablativos/administración & dosificación , Síndrome Nefrótico/terapia , Trasplante de Células Madre de Sangre PeriféricaRESUMEN
Antineutrophil cytoplasmic antibody-(ANCA) associated glomerulonephritis usually shows histopathologic features of pauciimmune crescentic glomerulonephritis and occurs late in life. We report a 14-year-old Japanese girl presenting with proteinuria, hematuria and mildly elevated serum creatinine. A renal biopsy specimen demonstrated crescentic glomerulonephritis, immunofluorescence showed mesangial IgA staining. Electron microscopic examination disclosed paramesangial deposits. Serum ANCA against myeloperoxidase (MPO) were detected at high titers. Myeloperoxidase-ANCA-related nephritis accompanied by IgA nephropathy is considered rare in childhood and teen years. Yet, if ANCA assays and detailed electron microscopic examination of renal specimens were performed routinely in patients with rapidly progressive glomerulonephritis, the diagnosis might be more frequent in young patients.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos , Mesangio Glomerular , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Inmunoglobulina A , Adolescente , Femenino , Mesangio Glomerular/química , Mesangio Glomerular/patología , Humanos , Inmunoglobulina A/análisisRESUMEN
We investigated the relationship between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and lipid metabolism in patients with nondiabetic chronic renal failure on hemodialysis. Serum from 181 nondiabetic patients on hemodialysis were examined. A genomic DNA fragment was amplified by polymerase chain reaction (PCR) for determining the ecNOS genotype. The PCR products were designated as a and b alleles by electrophoresis. In hemodialysis patients, the frequency of the ecNOS4 for b/b, b/a and a/a genotype was 76.6, 22.8 and 0.6%, respectively. There was not significant difference in the levels of total cholesterol (TC), triglyceride (TG) and calculated low-density lipoprotein cholesterol (LDL-c) in sera between patients (aa and ba) with the a allele and patients (bb) without the a allele. On the other hand, the levels of serum high-density lipoprotein cholesterol (HDL-c) in patients with the a allele (51.9 +/- 3.33 mg/dl) were significantly higher than those in patients without the a allele (43.05 +/- 1.40 mg/dl) (p = 0.005). The frequency of patients with the a allele and low levels of serum HDL-c among patients with a long duration of dialysis (> or =10 years) was significantly lower than that in patients with short duration of dialysis (<10 years) (p = 0.05). It appears that an intron 4 gene polymorphism in ecNOS may modulate lipid metabolism in nondiabetic patients on hemodialysis and the a allele of ecNOS gene polymorphism may affect the prognosis of hemodialysis patients with low levels of serum HDL-c.
Asunto(s)
Fallo Renal Crónico/genética , Fallo Renal Crónico/metabolismo , Lipoproteínas HDL/sangre , Óxido Nítrico Sintasa/genética , Polimorfismo Genético , Diálisis Renal , Alelos , Colesterol/sangre , Nefropatías Diabéticas , Femenino , Humanos , Intrones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III , Triglicéridos/sangreRESUMEN
Renal diseases of mixed connective tissue disease (MCTD) are not unusual. Although most of them are SLE-like renal impairment with immune complex deposits, systemic sclerosis- (SSc) like renal impairments with intimal thickening of interlobular arteries or arterioles are also encountered. Several cases of SSc complicated with MPO-ANCA-related necrotizing glomerulonephritis (nGN) are reported. Here we report a case which developed MPO-ANCA-related nGN 16 years after the diagnosis of MCTD. She exhibited pauci-immune focal nGN and significantly high titer of MPO-ANCA. She was successfully treated with prednisolone and cyclophosphamide. We believe this is the first case in which MPO-ANCA-related nGN was demonstrated in a patient with MCTD.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Glomerulonefritis/complicaciones , Enfermedad Mixta del Tejido Conjuntivo/complicaciones , Peroxidasa/inmunología , Femenino , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Humanos , Glomérulos Renales/patología , Persona de Mediana Edad , Enfermedad Mixta del Tejido Conjuntivo/inmunologíaRESUMEN
Many patients with type II mixed cryoglobulinemia have been shown to be infected with hapatitis C virus (HCV). Therefore, interferon-alfa has become the first choice of treatment for patients with HCV-associated cryoglobulinemia. However, the disease often relapses after the discontinuation of interferon therapy. The long-term effect of interferon therapy is controversial. Therefore, a more effective therapy needs to be developed. A 62-year-old Japanese woman was admitted to our hospital for the examination of abnormal liver function tests, severe edema, and purpura in her lower extremities. Glomerulopathy secondary to HCV-related cryoglobulinemia was suspected. Her serum creatinine was increased to 2.1 mg/dL. Interferon therapy was considered initially. However, because of pancytopenia caused by liver cirrhosis and splenomegaly, splenectomy was performed in February 1997, before the start of interferon therapy. Renal biopsy specimen taken at the time of the splenectomy showed typical cryoglobulinemic glomerulonephritis. Gradually, after surgery, the patient's thrombocytopenia and anemia improved, her proteinuria and hematuria were decreased, her cryocrit dropped from 15% to 5%, the Ccr increased from 21.1 mL/min to 48.8 mL/min, and the purpura in her lower extremities disappeared. A repeat renal biopsy performed in May 1998 showed marked histological improvement. Splenectomy is not widely accepted as a treatment for cryoglobulinemia. Our case suggests the possibility that the monoclonal-IgM component of the type II cryoglobulin may be formed in the spleen. In conclusion, splenectomy may be an effective therapy for cryoglobulinemia in patients with HCV-positive liver cirrhosis and pancytopenia secondary to splenomegaly.
Asunto(s)
Crioglobulinemia/clasificación , Glomerulonefritis/terapia , Esplenectomía , Anemia/terapia , Anticuerpos Monoclonales/inmunología , Biopsia , Creatinina/sangre , Crioglobulinemia/virología , Crioglobulinas/análisis , Femenino , Glomerulonefritis/etiología , Hematuria/terapia , Hepatitis C/complicaciones , Humanos , Inmunoglobulina M/inmunología , Cirrosis Hepática/etiología , Persona de Mediana Edad , Pancitopenia/etiología , Proteinuria/terapia , Bazo/inmunología , Esplenomegalia/etiología , Trombocitopenia/terapiaRESUMEN
We report autopsy findings of a 69-year-old man on long-term CAPD therapy for 13 years who showed linear peritoneal calcification. Continuous ambulatory peritoneal dialysis (CAPD) was started in 1982. He has been administered excessive amounts of vitamin D(3) derivatives (VitD) (2.0 to 2.5 microg daily) and calcium carbonate (4 g daily) for secondary hyperparathyroidism since initiation of CAPD. In May 1995, his intact parathyroid hormone (PTH) level increased over 1,000 pg/mL. Immediately after VitD was changed from pill to liquid, the dose was increased to 5 microg daily. Although the serum calcium level remained between 4.5 and 4.9 mEq/L, and serum phosphate level was 5.0 to 7.2 mg/dL, plain abdominal radiography and computed tomography showed continuous calcification along the intestinal wall in October 1995. In spite of the continuation of CAPD therapy, he remained asymptomatic until he died of congestive heart failure in January 1997. He experienced eight episodes of peritonitis during his clinical course. Autopsy showed that numerous calcified plaques were present on the submucosal portion between the thickened serosa and the longitudinal layer of the muscularis externa. The remainder of the subserosa was fibrotic, and the small arteries had markedly thickened intima and severely narrowed lumina.
Asunto(s)
Músculos Abdominales/patología , Calcinosis/etiología , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Músculos Abdominales/diagnóstico por imagen , Calcio/sangre , Carbonato de Calcio/uso terapéutico , Colecalciferol/uso terapéutico , Humanos , Hiperparatiroidismo Secundario/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Fosfatos/sangre , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
We report a patient with autosomal dominant polycystic kidney disease (ADPKD) undergoing long-term hemodialysis who underwent transcatheter arterial embolization (TAE) of the renal arteries to shrink enlarged kidneys. In 1983, the patient started hemodialysis because of chronic renal failure secondary to ADPKD. However, renal size continued to increase. In January 1997, he was admitted to our hospital with abdominal distension and anorexia, in addition to progression of anemia. Upper gastroendoscopy showed an esophageal ulcer and severe external compression of the stomach. Renal angiography using the Seldinger technique showed stretched and deformed segmental renal arteries with massive enlargement of the kidneys. TAE with stainless steel coils was performed on both renal arteries. With a rapid and progressive decrease in kidney size, anorexia and anemia were improved, and the gastrointestinal compression was eliminated. In some patients with ADPKD, renal size continues to increase even after the initiation of dialysis. In about 10 years, patients develop gastrointestinal complications, such as dysphagia, ileus, severe constipation, and intestinal perforation. Surgical procedures such as nephrectomy are not satisfactory. This report shows that TAE is a safe and effective therapy for patients with ADPKD with massively enlarged kidneys.
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Embolización Terapéutica , Fallo Renal Crónico/terapia , Riñón Poliquístico Autosómico Dominante/terapia , Arteria Renal , Diálisis Renal , Angiografía , Humanos , Hipertrofia , Riñón/patología , Fallo Renal Crónico/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Arteria Renal/diagnóstico por imagenAsunto(s)
Arginina/metabolismo , Fallo Renal Crónico/metabolismo , Óxido Nítrico/metabolismo , Nutrición Parenteral Total/efectos adversos , Anciano , Aminoácidos/sangre , Arginina/efectos adversos , Humanos , Hipotensión/inducido químicamente , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis RenalAsunto(s)
Eritropoyetina/administración & dosificación , Fallo Renal Crónico/enzimología , Óxido Nítrico Sintasa/genética , Diálisis Renal , Alelos , Anemia/etiología , Anemia/prevención & control , Femenino , Frecuencia de los Genes , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/genética , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
We report a case of 48-year old female with rheumatoid arthritis (RA) complicated with myasthenia gravis. In 1988, she was diagnosed of having RA, and several therapeutic drugs were administered, but her disease activity was in poor control. In July 1993, bucillamine (BU) was started at a dose of 100 mg/day, and her arthritis subsided. However, in October 1996, she was admitted with a rapidly progressive ptosis and double vision in the left eye, which became prominent in the evening. Because serum concentration of the antibody to acetylcholine receptors (AchR Ab) was elevated at 12.6 nmol/l, and the ptosis was reversed immediately after a tensilon test, ocular type myasthenia gravis (MG) was diagnosed and it was thought to have been induced by BU. Immunoadsorption therapy was started after discontinuation of this drug, and was continued for 6 months, resulting in improvement of neurological symptoms and decrease in AchR Ab level. MG has not recurred since. Although several cases of D-penicillamine (DP) induced MG are reported, only two cases are reported which were induced by BU, sulfhydryl compound which has a structure similar to DP. Since BU has been widely used as one of the disease modifying anti-rheumatic drugs in Japan, MG induced by this drug should be paid attention as one of the adverse effects.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Cisteína/análogos & derivados , Miastenia Gravis/inducido químicamente , Cisteína/efectos adversos , Femenino , Humanos , Técnicas de Inmunoadsorción , Persona de Mediana Edad , Miastenia Gravis/terapiaRESUMEN
We investigated the therapeutic effect of low density lipoprotein adsorption (LDL-A) in 14 patients who had focal glomerulosclerosis (FGS) with the nephrotic syndrome resistant to steroids. Patients received a total of 6 sessions (2 times a week for 3 weeks). The levels of total cholesterol, triglycerides and low-density lipoprotein were decreased significantly after treatment (by approximately 50%) in all patients (p<0.01). There also seemed to be a possibility that LDL-A improved the response to steroid therapy. The glomerular filtration rate (GFR) increased from 54.4 +/-27.4 ml/min to 70.0+/-30.2 ml/min (p <0.05) and daily urinary protein excretion (Up/day) decreased from 7.24+/-3.58 g/day to 2.56 + 2.00 g/day (p<0.01). Up/day was significantly higher in patients who showed more than 30% improvement of GFR (n = 6) than in patients who showed less than 30% improvement of GFR (n = 7) (9.50+/-3.41 g/day vs 4.59+/-1.17 g/day, p<0.05). The decrease of urinary protein excretion was more marked in younger patients (29.4+/-11.9 vs 49.7+/-14.8, p <0.05). Only electron microscopy was able to detect histological recovery in the patients who showed a decrease of proteinuria after LDL-A therapy and light microscopy was not able to verify or accurately identify the histological response. In conclusion, LDL-A seems to be effective for FGS associated with nephrotic syndrome resistant to steroids, especially in younger patients. Histological assessment of the effect of this treatment requires electron microscopic examination.
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Corticoesteroides/uso terapéutico , Glomeruloesclerosis Focal y Segmentaria/terapia , Lipoproteínas LDL/aislamiento & purificación , Adsorción , Adulto , Biopsia con Aguja , Eliminación de Componentes Sanguíneos , Terapia Combinada , Femenino , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Riñón/patología , Riñón/fisiopatología , Lipoproteínas LDL/sangre , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Síndrome Nefrótico/sangre , Síndrome Nefrótico/patología , Síndrome Nefrótico/fisiopatología , Síndrome Nefrótico/terapia , Proteinuria/orinaRESUMEN
We experienced a patient on continuous ambulatory peritoneal dialysis (CAPD) who showed hypererythropoietinemia (Epo concentration: 86.7 mU/ml, normal range: 8-36 mU/ml), erythrocytosis, high renin concentration (26.5 pg/ml) and chronic hypotension. In this patient the erythrocytosis progressed along with exacerbation of the chronic severe hypotensive state. This patient had systemic circulatory insufficiency as suggested by the fact that he had a fibrous myocardium and an increased anion gap. We hypothesized that circulatory insufficiency due to chronic severe hypotension may lead to the stimulation of the Epo production, due to a decreased oxygen supply to peripheral tissues and/or to the stimulation of the renin angiotensin system even in patients with end-stage renal failure.
Asunto(s)
Eritropoyetina/sangre , Hipotensión Ortostática/sangre , Diálisis Peritoneal Ambulatoria Continua , Renina/sangre , Anciano , Enfermedad Crónica , Resultado Fatal , Humanos , Hipotensión Ortostática/patología , Hipotensión Ortostática/terapia , Riñón/patología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Masculino , Miocardio/patologíaRESUMEN
Nitric oxide (NO) synthesized by the vascular endothelium regulates mammalian blood vessels and other systems in humans. Recently, an endothelial nitric oxide synthase (ecNOS) gene polymorphism, the 27-bp repeat in intron 4 (ecNOS4), was reported to be related to the pathogenesis of coronary heart disease and terminal renal failure. We analyzed this polymorphism in a group of 413 healthy subjects, and measured their plasma nitrite and nitrate (NOx) levels. The frequency of the b allele was 89.8% , and the frequency of the a allele was 10.2%. The frequency of ecNOS4 b/b, ecNOS4 b/a, and ecNOS4 a/a in the healthy subjects in this study was 0.814 (n=336), 0.169 (n=70) and 0.017 (n=7), respectively. Using this polymorphism as a DNA marker, we found a strong association between the alleles of the ecNOS gene polymorphism and the plasma NOx levels. The basal NO metabolite levels were 28.8 micromol/L in subjects with ecNOS4 a/a, 31.4 micromol/L in those with ecNOS4 b/a, and 35.5 micromol/L in those with ecNOS4 b/b. The mean plasma NOx level of the subjects who were homozygous for the a allele was nearly 20% lower than in the subjects with the b allele. The plasma NOx level of the subjects with the a allele was 31.2+/-2.00 micromol/L, and significantly lower than the 35.5+/-0.93 micromol/L in those without the a allele (P <0.05). The results of this study indicate that the ecNOS4 gene locus may be responsible for variations in the genetic control of plasma NOx and that analysis of ecNOS4 gene polymorphism may be a useful tool for studying the relation between NO and diseases.