RESUMEN
Glomerular inflammation is a putative aggravation factor for type 2 diabetic nephropathy and urinary thrombin is a novel marker of glomerular inflammation. To clarify the relationship between glomerular inflammation and progression of the nephropathy, we measured urinary thrombin in 118 patients with type 2 diabetic nephropathy at different stages. To investigate the implications of urinary thrombin in the nephropathy, we compared urinary thrombin with expression of tissue factor, the trigger of blood coagulation activation, in glomeruli and with markers of renal injury (estimated glomerular filtration rate (eGFR) and proteinuria). Urinary thrombin was found in 4.9% (3/61), 0.0% (0/12), 29.6% (8/27) and 50.0% (9/18) of patient groups at stages 1, 2, 3 and 4, respectively. Thus, urinary thrombin was negligible in the patients at early stages (stages 1 and 2), but was present predominantly in the patients at advanced stages (stages 3 and 4). Tissue factor was expressed in accumulated macrophages in glomeruli, which indicates that thrombin may be generated in inflamed glomeruli presumably via inflammation-induced activation of the exudated coagulation factors into glomerular tissues and then be excreted in urine. Urinary thrombin was significantly associated with both decreased eGFR and increased proteinuria in type 2 diabetic nephropathy. Therefore, increased urinary thrombin in patients with advanced stages of type 2 diabetic nephropathy suggests that glomerular inflammation may injure the tissues, thereby impairing renal function. Monitoring an effect of anti-diabetic treatments on glomerular inflammation in the patients with type 2 diabetic nephropathy may be a possible application of urinary thrombin.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/orina , Inflamación/complicaciones , Inflamación/orina , Glomérulos Renales/patología , Trombina/orina , Antitrombina III/metabolismo , Biomarcadores/orina , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Inflamación/sangre , Inflamación/fisiopatología , Glomérulos Renales/fisiopatología , Masculino , Persona de Mediana Edad , Péptido Hidrolasas/metabolismo , Proteinuria/complicaciones , Proteinuria/fisiopatología , Tromboplastina/metabolismoRESUMEN
INTRODUCTION: Mortality in hemodialysis patients is relatively high; thus, its risk stratification is very important. There are insufficient data describing the current status of the management of serum phosphate and calcium levels. METHODS: We conducted a multicenter, prospective, registry study throughout the Kumamoto Prefecture in Japan. We enrolled 1993 patients at 58 facilities with complete explanatory data, including serum phosphate, corrected calcium, and intact parathyroid hormone levels. We categorized subjects into nine categories according to low, normal, and high levels of phosphate and corrected calcium levels. The endpoint was all-cause mortality. RESULTS: Of the total number of subjects, 56.1% of the patients were in the normal phosphate and calcium category, and 72% and 77.1% had controlled serum phosphate and calcium levels, respectively. Two hundred twenty-six deaths occurred during the follow-up period. In the nine categories, the highest mortality rates were observed in the highest corrected calcium and lowest phosphate categories. Stepwise backward multivariate regression analyses identified the serum corrected calcium level (OR, 1.38; 95% CI, 1.06-1.79; P = 0.016) and the serum phosphate level (OR, 1.26; 95% CI, 1.08-1.48; P = 0.003) as significant and independent predictors of all-cause mortality. CONCLUSIONS: The corrected serum calcium and phosphate levels are associated with mortality in our dialysis population, with poorest survival in patients with high corrected serum calcium and low serum phosphorus.
Asunto(s)
Calcio/sangre , Fósforo/sangre , Diálisis Renal/efectos adversos , Anciano , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diálisis Renal/métodos , Resultado del TratamientoRESUMEN
A 58-year-old man was referred to our institution for an evaluation of nephrotic range proteinuria. Renal biopsy showed a marked expansion of the mesangial matrix and thickening of glomerular basement membrane (GBM) in periodic acid-silver methenamine (PAM). Immunofluorescence (IF) revealed strong staining for the monoclonal kappa light chain. EM demonstrated massive subendothelial and mesangial dense deposits. As a result, light chain deposition disease (LCDD) was diagnosed. Melphalan and prednisolone (MP) therapy was started, which was continued for 10 years with minimal complications. Serial evaluations of renal histology revealed the resolution of nodular lesions and the glomeruli became nearly normal. MP therapy can therefore be an effective therapeutic option for LCDD if it is continued over the long term.
Asunto(s)
Membrana Basal Glomerular/patología , Mesangio Glomerular/patología , Cadenas kappa de Inmunoglobulina/metabolismo , Paraproteinemias/patología , Proteinuria/patología , Antineoplásicos Alquilantes/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Paraproteinemias/tratamiento farmacológico , Paraproteinemias/metabolismo , Prednisolona/uso terapéutico , Proteinuria/metabolismoRESUMEN
BACKGROUND: Crescentic glomerulonephritis (CresGN), an uncommon rapidly progressive disease, is characterized by severe glomerular inflammation with fibrin deposition. The lack of specific CresGN biomarkers delays diagnosis and threatens life. Because fibrin deposits in CresGN glomeruli indicate thrombin generation, we hypothesized that thrombin is excreted in urine and is a specific CresGN biomarker. METHODS: We measured urinary thrombin activity in 200 untreated patients (17 with CresGN, 183 with primary glomerulonephritis) and controls (8 patients with healed CresGN, 11 with nephrosclerosis, and 10 with tubulointerstitial nephritis, and 66 healthy volunteers). CresGN types included 15 pauci-immune and 2 immune complex. We assessed the diagnostic accuracy of thrombinuria in 169 patients with hematuria and proteinuria. Renal biopsy tissues were immunostained for tissue factor and fibrin. We analyzed the relationship of thrombinuria to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, glomerular fibrin deposition, antineutrophil cytoplasmic antibodies (ANCAs), and C-reactive protein (CRP). We studied changes in thrombin activities after glucocorticoid treatment in 12 patients with thrombinuria. RESULTS: The highest thrombinuria occurrence was in CresGN (70.6%), followed by membranoproliferative glomerulonephritis (41.7%), IgA nephropathy (9.2%), and acute glomerulonephritis (0%). More than 75% of patients with nonproliferative glomerulonephritis manifested no thrombinuria. No controls had thrombinuria. Thrombinuria showed high CresGN specificity (90.1%) and moderate sensitivity (70.6%) and was detected in 4 of 7 patients with ANCA-negative CresGN. In CresGN, thrombinuria was associated with fibrin deposition in glomerular extracapillary tissue, where monocytes/macrophages expressed tissue factor. Thrombinuria in CresGN was unrelated to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, and CRP. After glucocorticoid treatment, thrombinuria in patients with CresGN rapidly disappeared but proteinuria and hematuria persisted. CONCLUSIONS: Thrombinuria was specific for glomerular inflammation, was unaffected by systemic inflammation or coagulation, and demonstrated good diagnostic accuracy for CresGN including ANCA-negative cases. Thrombinuria measurement may provide risk-free diagnosis and screening for CresGN.
Asunto(s)
Biomarcadores/orina , Glomerulonefritis/diagnóstico , Trombina/orina , Anciano , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/fisiopatología , Glomerulonefritis/orina , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Tromboplastina/metabolismoRESUMEN
We report a Japanese woman with variegate porphyria accompanied by amyloid A (AA) amyloidosis. Arthropathy involving multiple joints occurred at 35 years old and persisted. C-reactive protein was 4.0 mg/dL, but rheumatoid factor was negative. Radiographs did not reveal any loss or narrowing of the joint spaces. Two years later, blister formation after sun exposure and reddish urine were first noted. At the age of 45 years, she developed abdominal pain, nausea, vomiting and seizures. After administration of phenobarbital, reddish urine was noted and muscular weakness progressed to atonic quadraparesis. Porphyria attack was diagnosed from high urinary levels of ∂ aminolevulinic acid and porphobilinogen. At the age of 47 years, hemodialysis was started. At the age of 49 years, progression of her gastrointestinal event resulted in death. Autopsy showed massive deposits of AA amyloidosis in various organs, including the kidneys and digestive tract. Thus, amyloid deposition may have contributed to both end-stage renal failure and her gastrointestinal symptoms. This is the first report about the coexistence of porphyria and AA amyloidosis. Chronic inflammation related to this patient's seronegative arthropathy, although atypical for porphyria, might have contributed to the development of AA amyloidosis.
Asunto(s)
Amiloidosis/complicaciones , Porfiria Variegata/diagnóstico , Adulto , Resultado Fatal , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Fallo Renal Crónico/complicaciones , Proteína Amiloide A Sérica/metabolismoRESUMEN
A 66-year-old woman with seropositive rheumatoid arthritis (RA) and latent tuberculosis infection developed minimal-change nephrotic syndrome following the initiation of anti-tuberculosis chemoprophylaxis with isoniazid. This is the first reported case of an isoniazid-induced nephrotic syndrome. Isoniazid as a single-drug intervention is widely accepted as a safe and effective means of anti-tuberculosis chemoprophylaxis, particularly for RA patients with latent tuberculosis infection; the present case, however, demonstrates that isoniazid has the potential to induce minimal-change nephrotic syndrome, even when used as a single-drug intervention.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Isoniazida/efectos adversos , Isoniazida/uso terapéutico , Tuberculosis Latente/prevención & control , Anciano , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Artritis Reumatoide/epidemiología , Quimioprevención , Comorbilidad , Femenino , Glucocorticoides/uso terapéutico , Humanos , Tuberculosis Latente/epidemiología , Nefrosis Lipoidea/inducido químicamente , Nefrosis Lipoidea/diagnóstico , Nefrosis Lipoidea/tratamiento farmacológico , Prednisolona/uso terapéutico , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND/AIMS: A dialyzer (APS-EX) with a higher hollow fiber density ratio was manufactured using the highest performance polysulfone hollow fiber from Asahi-Kasei Medical. METHODS: We compared the performance of this device in comparison with hemodialysis (HD; APS-S) and hemodiafiltration (HDF) conditions (APS-S, 10 l post-HDF) to evaluate its merit as an internal filtration-enhanced dialyzer. RESULTS: With low molecular weight proteins, APS-EX had a reduction ratio of 74.3% for beta(2)-microglobulin (beta(2)-MG), and 31.0% for alpha(1)-MG. APS-EX had a significant higher removal amount of alpha(1)-MG compared to APS-S (HDF). Significant differences were seen in albumin loss, 4.0 g for APS-EX, 3.0 g for APS-S (HDF), and 0.9 g for APS-S (HD). Using HD mode, APS-EX demonstrated a performance which was more than equivalent to approximately 10 l post-HDF. CONCLUSIONS: The results suggested the possibility that HD equivalent to HDF can be performed safely with the ultrapure dialysate when using APS-EX with internal filtration.
Asunto(s)
Proteínas Sanguíneas/aislamiento & purificación , Hemodiafiltración/instrumentación , Hemodiafiltración/normas , Polímeros/farmacología , Sulfonas/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Albúminas/aislamiento & purificación , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , Diálisis Renal , alfa-Macroglobulinas/aislamiento & purificación , Microglobulina beta-2/aislamiento & purificaciónRESUMEN
Chronic inflammation contributes to the pathogenesis of several complications of hemodialysis therapy. It is thought that backfiltration of bacteria-derived contaminations during dialysis may induce a chronic inflammatory state. High-sensitivity C-reactive protein (hs-CRP) is one of the tools which can take a hold on such a chronic inflammatory condition. We examined the effect of ultrapure dialysate which contributes to chronic inflammation with hs-CRP and tried to reduce endotoxin (ET) levels at the end of the dialysate from 70 EU/l to <1.0 EU/l (ultrapure dialysate). Other dialysis conditions, except ET level, were fixed. We investigated the hs-CRP of 23 patients receiving regular dialysis before the use of ultrapure dialysate and 1 year after use of it prospectively. The data showed a significant decrease in the median value of the hs-CRP from 0.16 to 0.07 mg/dl (p < 0.05). The value of serum beta(2)-microglobulin decreased from 33.2 to 28.4 mg/dl (p < 0.01) and the hemoglobin level increased from 10.0 to 11.0 g/dl (p < 0.05). These results indicate that even a dialysate containing 70 EU/l of ET level may induce a chronic inflammatory state. hs-CRP is a very useful marker of chronic inflammation and the use of ultrapure dialysate is necessary to improve a chronic inflammatory state. The targeted ET level at the end of the dialysate should be set at < or = 1.0 EU/l.
Asunto(s)
Soluciones para Diálisis/normas , Inflamación/prevención & control , Diálisis Renal/efectos adversos , Anciano , Proteína C-Reactiva/análisis , Enfermedad Crónica , Endotoxinas/análisis , Femenino , Hemoglobinas/análisis , Humanos , Inflamación/etiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Control de Calidad , Esterilización , Microglobulina beta-2/sangreRESUMEN
BACKGROUND: Mutations of the NPHS2 gene are responsible for autosomal-recessive steroid-resistant nephrotic syndrome. Its product, podocin, faces the slit diaphragm area with its two ends in the cytoplasm of foot processes. METHODS: We generated rabbit polyclonal antibodies against conjugated peptides from human podocin N- and C-termini, and studied podocin and synaptopodin using kidney tissues of normal humans and those with glomerular diseases. RESULTS: Antipodocin antibodies detected the original 42 kD fragment and an extra smaller fragment by Western blot analysis using human isolated mature glomeruli. RNA analysis showed two bands, the original and the other of a decreased length. Immunohistochemically, podocin was detected in a linear pattern along the glomerular capillary loop. Antipodocin antibody (C-terminal) stained the smooth muscles of renal arterioles and aorta. Among 42 patients, podocin was normally expressed in glomeruli in purpura nephritis, IgA nephropathy (IgAN), and minimal-change disease (MCD), while it was either decreased or absent in most subjects with focal segmental glomerulosclerosis (FSGS). The expression of synaptopodin was similar to that of podocin, although some discrepancy existed. CONCLUSION: Although indirect, our data suggest the existence of a vascular isoform of podocin with a different molecular mass. We propose that examination of podocin expression may help differentiate MCD from FSGS.