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BACKGROUND: Although vaccination has been reported to reduce the morbidity and severity of COVID-19 infection in patients with kidney disease, gross hematuria is frequently reported following vaccination in patients with IgA nephropathy. We investigated the frequency of gross hematuria following COVID-19 vaccination and its effect on renal function in IgA nephropathy patients. METHODS: Adverse reactions after two or more COVID-19 vaccine doses were investigated in 295 IgA nephropathy patients attending Osaka Cty general hospital from September 2021 to November 2022. We compared differences in background characteristics and other adverse reactions between groups with and without gross hematuria after vaccination, and examined changes in renal function and proteinuria. RESULTS: Twenty-eight patients (9.5%) had gross hematuria. The median age of patients with and without gross hematuria was 44 (29-48) and 49 (42-61) years, respectively, indicating a significant difference. The percentage of patients with microscopic hematuria before vaccination differed significantly between those with (65.2%) and without (32%) gross hematuria. Adverse reactions, such as fever, chills, headache and arthralgia, were more frequent in patients with gross hematuria. There was no difference in renal functional decline after approximately 1 year between patients with and without gross hematuria. We also found no significant changes in estimated glomerular filtration rate or proteinuria before and after vaccination in the gross hematuria group. However, some patients clearly had worsening of renal function. CONCLUSIONS: While COVID-19 vaccination is beneficial, care is required since it might adversely affect renal function in some patients.
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Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors were developed for treatment of renal anemia. Patients applicable for HIF-PHD inhibitor treatment experience complications such as chronic kidney disease, whereby water and electrolyte homeostasis is disrupted. The effects of hypoxia-inducible factor stabilization on salt accumulation in the setting of reduced renal function remain unclear. In the present study, we investigated the effect of a HIF-PHD inhibitor, molidustat, on salt distribution and excretion in rats with subtotal nephrectomy-induced chronic kidney disease. Male Wistar rats were subjected to 5/6 nephrectomy. After confirming blood pressure elevation (>150 mmHg, at 4 weeks after surgery), rats were treated with molidustat. After 1 week of treatment, molidustat did not significantly improve blood cell volume or blood pressure. Distribution of sodium, potassium, and water in skin, carcass, and bone samples was not affected by molidustat. Furthermore, molidustat had no significant effect on urinary sodium excretion or concentration in response to acute oral salt loading (1 g/kg). In conclusion, molidustat did not affect distribution or excretion of salt in rats subjected to a model of nephron loss.
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Hipertensión/metabolismo , Nefrectomía/efectos adversos , Inhibidores de Prolil-Hidroxilasa/farmacología , Pirazoles/farmacología , Insuficiencia Renal Crónica/metabolismo , Sodio/metabolismo , Triazoles/farmacología , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Masculino , Ratas Wistar , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatología , Sodio/orinaRESUMEN
We examined the effects of the angiotensin receptor-neprilysin inhibitor LCZ696 on overt proteinuria and renal injury in type 2 diabetic Otsuka-Long- Evans-Tokushima-Fatty (OLETF) rats. Aged OLETF rats were also treated with either valsartan or valsartan plus hydralazine for comparison. LCZ696 caused greater attenuation of the progression of proteinuria than either valsartan alone or valsartan combined with hydralazine. Reduced glomerular injury and tubulointerstitial fibrosis were also observed in LCZ696-treated rats. Moreover, LCZ696 prevented increases in blood urea nitrogen (BUN) and creatinine levels. These data suggest that LCZ696 elicits a reno-protective effect against type 2 diabetes with overt proteinuria.
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Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Tetrazoles/uso terapéutico , Animales , Compuestos de Bifenilo , Combinación de Medicamentos , Ratas , Ratas Endogámicas OLETF , ValsartánRESUMEN
We aimed to examine the effects of a sodium glucose co-transporter 2 (SGLT2) inhibitor on systemic and intrarenal renin-angiotensin system (RAS) in subtotally nephrectomized non-diabetic rats, a model of chronic kidney disease (CKD). Oral administration of the selective SGLT2 inhibitor, TA-1887 (10 mg/kg/day), for 10 weeks induced glycosuria. However, plasma renin activity, plasma angiotensinogen levels, kidney angiotensin II contents and renal injury were not significantly affected by TA-1887. These data indicate that chronic treatment with an SGLT2 inhibitor does not activate the systemic and intrarenal RAS in subjects with non-diabetic CKD.
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Glucósidos/uso terapéutico , Indoles/uso terapéutico , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Administración Oral , Angiotensina II/metabolismo , Angiotensinógeno/sangre , Animales , Modelos Animales de Enfermedad , Glucosuria/inducido químicamente , Masculino , Nefrectomía , Ratas Sprague-Dawley , Renina/sangre , Transportador 2 de Sodio-GlucosaRESUMEN
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.
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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 TiempoAsunto(s)
Nefritis Lúpica/diagnóstico por imagen , Podocitos/ultraestructura , Adulto , Anticuerpos Antifosfolípidos/sangre , Antirreumáticos , Enfermedad de Fabry/diagnóstico por imagen , Humanos , Hidroxicloroquina , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/etiología , Masculino , Microscopía ElectrónicaRESUMEN
Osteoporosis is defined as a condition of impairment in bone strength and predisposes individuals to an increased risk of fractures. The risk of fragility fracture is shown to be high in patients with chronic kidney disease (CKD). Osteoporosis treatment for patients with CKD G1-3 should not differ from treatment for patients without CKD, as long as there are no accompanying hyperparathyroidism and hyperphosphatemia that indicate the co-existence of CKD -mineral and bone disorder. However, there are few published data on osteoporosis treatment for patients with CKD G4, 5. So, considerations for current pharmacologic therapy (such as bisphosphonate, denosumab, teriparatide, and raloxifene) should be a thoughtful and open discussion with these patients.
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Osteoporosis/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Humanos , Osteoporosis/etiología , Índice de Severidad de la EnfermedadRESUMEN
Renal denervation has attracted attention as a novel antihypertensive treatment for hypertensive patients who are poorly controlled by medicine. Clinical studies have shown the antihypertensive effects of renal denervation in patients with treatment-resistant hypertension. However, renal denervation potentially has other beneficial effects, such as improving glucose metabolism and cardioprotection beyond its antihypertensive effects. In this mini-review article, we summarize and discuss the effects of renal denervation on proteinuria, albuminuria, and renal function based on the recent findings of clinical studies, and review the renoprotective effects of renal denervation.
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Although recent studies have proven that renin-angiotensin system (RAS) blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS) are important for intrarenal angiotensinogen (AGT) augmentation in the progression of diabetic nephropathy. However, no direct evidence is available to demonstrate that AGT expression is enhanced in the kidneys of patients with diabetes. To examine whether the expression levels of ROS- and RAS-related factors in kidneys are increased with the progression of diabetic nephropathy, biopsied samples from 8 controls and 27 patients with type 2 diabetes were used. After the biopsy, these patients were diagnosed with minor glomerular abnormality or diabetes mellitus by clinical and pathological findings. The intensities of AGT, angiotensin II (Ang II), 4-hydroxy-2-nonenal (4-HNE), and heme oxygenase-1 (HO-1) were examined by fluorescence in situ hybridization and/or immunohistochemistry. Expression levels were greater in patients with diabetes than in control subjects. Moreover, the augmented intrarenal AGT mRNA expression paralleled renal dysfunction in patients with diabetes. These data suggest the importance of the activated oxidative stress/AGT/RAS axis in the pathogenesis of diabetic nephropathy.
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Angiotensinógeno/metabolismo , Nefropatías Diabéticas/genética , Estrés Oxidativo/genética , Sistema Renina-Angiotensina/genética , Adulto , Aldehídos/metabolismo , Angiotensinógeno/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Femenino , Hemo-Oxigenasa 1/metabolismo , Humanos , Riñón/metabolismo , Riñón/patología , Masculino , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to examine the efficacy of tonsillectomy on remission and progression of IgA nephropathy. METHODS: We conducted a single-center 7-year historical cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as disappearance of urine abnormalities at two consecutive visits, glomerular filtration rate (GFR) decline defined as 30% GFR decrease from baseline and GFR slope during the follow-up. RESULTS: Seventy of the 200 patients received tonsillectomy. Tonsillectomy was associated with increased incidence of clinical remission (P+0.01, log-rank test) and decreased incidence of GFR decline (P=0.01, log-rank test). After adjustment for age and gender, hazard ratios in tonsillectomy were 3.90 (95% confidence interval 2.46-6.18) for clinical remission and 0.14 (0.02-1.03) for GFR decline. After further adjustment for laboratory (baseline mean arterial pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion, endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin-angiotensin system inhibitors), similar results were obtained in each model. Even after exclusion of 69 steroid-treated patients, results did not change. GFR slopes in tonsillectomy and non-tonsillectomy groups were 0.60±3.65 and -1.64±2.59 mL/min/1.73 m2/year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P=0.01). CONCLUSION: Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration even in non-steroid-treated patients.
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Antiinflamatorios/uso terapéutico , Glomerulonefritis por IGA/terapia , Prednisolona/uso terapéutico , Tonsilectomía , Adulto , Presión Arterial , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/mortalidad , Glomerulonefritis por IGA/patología , Hematuria/diagnóstico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pronóstico , Proteinuria/diagnóstico , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
Focus on the role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of hypertension and renal damage has shifted recently to the role of the local RAAS in the kidneys. Inappropriate augmentation of intrarenal RAAS activity in patients with chronic kidney disease has suggested playing important roles in the development of hypertension and renal injury. In this article, I show the recent findings that salt-induced this augmentation may contribute to the development of salt-sensitive hypertension and play a key role in cardiorenal syndrome (CRS), and that blockade of intrarenal RAAS may be an important strategy for salt-sensitive hypertension and CRS.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Sales (Química)/metabolismo , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Renal Crónica/metabolismoRESUMEN
BACKGROUND: A potential contribution of local activation of the renin-angiotensin system (RAS) to the pathogenesis of renal injury has been indicated by evidence for blood pressure-independent renoprotective effects of angiotensin II (AngII) receptor blockers (ARBs). The present study was performed to test the hypothesis that urinary angiotensinogen provides a specific index of intrarenal RAS status in patients with immunoglobulin A (IgA) nephropathy. METHODS: This paper is a survey of urine specimens from three groups: healthy volunteers, patients with IgA nephropathy and patients with minor glomerular abnormality (MGA). Patients with hypertension, diabetes, reduced glomerular filtration rate and/or who were under any medication were excluded from this study. Urinary angiotensinogen levels were measured by a sandwich enzyme-linked immunosorbent assay system. RESULTS: Urinary angiotensinogen levels were not different between healthy volunteers and patients with MGA. However, urinary angiotensinogen levels, renal tissue angiotensinogen expression and AngII immunoreactivity were significantly higher in patients with IgA nephropathy than in patients with MGA. Baseline urinary angiotensinogen levels were positively correlated with renal angiotensinogen gene expression and AngII immunoreactivity but not with plasma renin activity or the urinary protein excretion rate. In patients with IgA nephropathy, treatment with an ARB, valsartan (40 mg/day), significantly increased renal plasma flow and decreased filtration fraction, which were associated with reductions in urinary angiotensinogen levels. CONCLUSION: These data indicate that urinary angiotensinogen is a powerful tool for determining intrarenal RAS status and associated renal derangement in patients with IgA nephropathy.
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Angiotensinógeno/orina , Biomarcadores/orina , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis por IGA/orina , Sistema Renina-Angiotensina/fisiología , Presión Sanguínea , Estudios de Casos y Controles , Creatinina/orina , Ensayo de Inmunoadsorción Enzimática , Femenino , Tasa de Filtración Glomerular , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana EdadRESUMEN
Treatment with angiotensin II type 1 receptor blockers (ARBs) is the first-line therapy for hypertensive patients with diabetic nephropathy. However, emerging clinical evidence indicates that mineralocorticoid receptor (MR) blockers have blood pressure-independent antiproteinuric effects. We sought to determine whether treatment with an MR blocker, eplerenone, enhances the effects of an ARB, telmisartan, on podocyte injury and proteinuria in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. From 20 to 50 weeks old, diabetic OLETF rats showed higher systolic blood pressure (SBP) and urinary protein excretion (U(protein)V) than nondiabetic control Long-Evans-Tokushima-Otsuka rats. At 50 weeks old, OLETF rats also showed glomerular sclerosis and podocyte injury, whereas nephrin and podocin mRNA levels in isolated glomeruli were significantly decreased. Treatment with telmisartan (3 mg/kg/day p.o.) decreased SBP and U(protein)V, increased nephrin and podocin mRNA levels, and attenuated glomerular sclerosis and podocyte injury. Eplerenone (100 mg/kg/day p.o.) did not alter SBP but elicited similar changes in renal parameters. However, greater reductions in U(protein)V and podocyte injury and greater increases in nephrin and podocin mRNA levels were observed in the combination treatment group. Hydralazine (25 mg/kg/day p.o.) decreased SBP but did not alter any renal parameters. These data indicate that MR blockade enhances the SBP-independent antiproteinuric effect of an ARB through inhibiting podocyte injury in type 2 diabetic rats.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides , Podocitos/efectos de los fármacos , Proteinuria/tratamiento farmacológico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Benzoatos/farmacología , Benzoatos/uso terapéutico , Diabetes Mellitus Tipo 2/patología , Sinergismo Farmacológico , Eplerenona , Péptidos y Proteínas de Señalización Intracelular , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Masculino , Proteínas de la Membrana/biosíntesis , Podocitos/patología , Proteinuria/etiología , Ratas , Ratas Endogámicas OLETF , Espironolactona/análogos & derivados , Espironolactona/farmacología , Espironolactona/uso terapéutico , TelmisartánRESUMEN
AIMS/INTRODUCTION: Clinical studies have shown that treatment with inhibitors of sodium-glucose cotransporter 2 (SGLT2) significantly increases the hematocrit in patients with type 2 diabetes. To investigate whether SGLT2 inhibitors directly promote erythropoietin production independently on blood glucose reduction, the hematopoietic effect of the specific SGLT2 inhibitor, luseogliflozin, was examined in non-diabetic rats with renal anemia. MATERIALS AND METHODS: Renal anemia was induced by treatment with adenine (200 or 600 mg/kg/day, orally for 10 days) in non-diabetic Wistar-Kyoto or Wistar rats, respectively. Luseogliflozin (10 mg/kg bodyweight) or vehicle (0.5% carboxymethyl cellulose) was then administered for 6 weeks. The hematocrit and the hemoglobin (Hb), blood urea nitrogen, plasma creatinine, and plasma erythropoietin levels were monitored. RESULTS: Treatment with adenine decreased the hematocrit and the Hb level, which were associated with increases in the blood urea nitrogen and plasma creatinine levels. In Wistar-Kyoto rats treated with 200 mg/kg/day adenine, administration of luseogliflozin induced glycosuria, but did not change the blood urea nitrogen, plasma creatinine levels, hematocrit, Hb or plasma erythropoietin levels. Similarly, luseogliflozin treatment failed to change the hematocrit or the Hb levels in Wistar rats with renal anemia induced by 600 mg/kg/day of adenine. Plasma erythropoietin concentrations were also not different between luseogliflozin- and vehicle-treated rats. Similarly, in human erythropoietin-producing cells derived from pluripotent stem cells, luseogliflozin treatment did not change the erythropoietin level in the medium. CONCLUSIONS: These data suggest that SGLT2 inhibitor fails to exert hematopoietic effects in non-diabetic conditions.
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Anemia/tratamiento farmacológico , Células Madre Hematopoyéticas/efectos de los fármacos , Insuficiencia Renal/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Sorbitol/análogos & derivados , Adenina , Anemia/sangre , Anemia/inducido químicamente , Animales , Modelos Animales de Enfermedad , Eritropoyetina/sangre , Hematócrito , Hemoglobinas/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas WKY , Ratas Wistar , Insuficiencia Renal/sangre , Insuficiencia Renal/inducido químicamente , Sorbitol/farmacologíaRESUMEN
We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.
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Presión Sanguínea/fisiología , Fenómenos Fisiológicos Cardiovasculares , Metabolismo Energético/fisiología , Frecuencia Cardíaca/fisiología , Riñón/inervación , Sodio en la Dieta , Sistema Nervioso Simpático/fisiología , Animales , Sistema Cardiovascular , Masculino , Ratas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , TelemetríaRESUMEN
OBJECTIVES: Beneficial effects of angiotensin II type 1 receptor blockers have been indicated for patients with diabetic nephropathy. We investigated the effects of an angiotensin II type 1 receptor blocker, telmisartan, on intrarenal angiotensin II levels and the progression of albuminuria or glomerular injury in type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats with microalbuminuria. METHODS AND RESULTS: Otsuka Long-Evans Tokushima Fatty rats were randomly treated with telmisartan (10 mg/kg/day, orally), hydralazine (25 mg/kg/day in drinking water) or vehicle from the initiation of albuminuria (13 weeks old). At this age, Otsuka Long-Evans Tokushima Fatty rats showed low but detectable albuminuria (1.0 +/- 0.1 mg/day) and higher systolic blood pressure, postprandial blood glucose and kidney angiotensin II levels than age-matched nondiabetic Long-Evans Tokushima Otsuka rats. At 35 weeks of age, vehicle-treated Otsuka Long-Evans Tokushima Fatty rats did not show apparent glomerular injury or tubulointerstitial fibrosis but did exhibit severe albuminuria (72.6 +/- 5.9 mg/day) and accumulation of cytoplasmic granules containing albumin in podocytes. Otsuka Long-Evans Tokushima Fatty rats also showed higher systolic blood pressure, postprandial blood glucose, collagen gene expression, desmin staining (a marker of podocyte injury) and angiotensin II levels than Long-Evans Tokushima Otsuka rats. Treatment with telmisartan did not affect postprandial blood glucose but decreased systolic blood pressure, collagen gene expression, desmin staining and angiotensin II levels. Telmisartan also prevented the development of albuminuria (0.6 +/- 0.1 mg/day at 35 weeks old) and accumulation of cytoplasmic granules. Hydralazine treatment resulted in a similar reduction in systolic blood pressure and partially attenuated the albuminuria (35.4 +/- 1.8 mg/day at 35 weeks old) but did not affect the other parameters. CONCLUSION: The present results suggest the contribution of augmented intrarenal angiotensin II levels to the initiation and progression of albuminuria as well as podocyte abnormalities in type 2 diabetic rats. Angiotensin II blockade may inhibit the transition from microalbuminuria to overt nephropathy through prevention of intrarenal angiotensin II augmentation, independently of changes in blood pressure and glucose levels.
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Albuminuria/tratamiento farmacológico , Angiotensina II/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bencimidazoles/farmacología , Benzoatos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Albuminuria/metabolismo , Albuminuria/patología , Animales , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Colágeno/genética , Colágeno/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Hipertensión Renal/patología , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Corteza Renal/patología , Masculino , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas OLETF , TelmisartánRESUMEN
Several investigators have reported chymase-positive mast cells in tubulointerstitial damage. However, the significance of the presence of chymase in the pathophysiology of renal diseases is unclear. We investigated relationships among chymase, renal damage, and intra-renal circulation. The participant pool consisted of 52 patients with immunoglobulin A (IgA) nephropathy who underwent renal biopsy. Of these, 18 were examined before and 2 months after the initiation of treatment with prednisolone alone (n=9) or combined with the angiotensin II receptor blocker valsartan (n=9). Biopsied renal specimens were evaluated, and the degree of renal circulation (resistive index; RI) was calculated by measuring flow velocity using Doppler sonography. The number of chymase-positive mast cells as visualized by immunohistochemical staining correlated significantly with both tubulointerstitial damage (rho=0.69, p<0.001) and RI (r=0.52, p<0.001). Treatment with prednisolone combined with valsartan effectively decreased both chymase-positive mast cells and RI, displaying a significant correlation between these biomarkers (rho=0.85, p=0.016). However, no such effect was observed with prednisolone alone. The severity of tubulointerstitial damage and the degree of proteinuria were similar in both treatment groups throughout the study term. We concluded that the presence of chymase-positive mast cells and the associated decrease in renal circulation corresponded to disease progression in IgA nephropathy. Combination therapy using prednisolone and valsartan may lead to improvements in intra-renal circulation and to interference in the recruitment of chymase-positive mast cells.
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Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Mastocitos/efectos de los fármacos , Prednisolona/administración & dosificación , Circulación Renal/efectos de los fármacos , Tetrazoles/administración & dosificación , Valina/análogos & derivados , Adolescente , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Antiinflamatorios/administración & dosificación , Antihipertensivos/administración & dosificación , Biopsia , Quimasas/metabolismo , Quimioterapia Combinada , Femenino , Glomerulonefritis por IGA/inmunología , Humanos , Riñón/diagnóstico por imagen , Riñón/inmunología , Riñón/patología , Modelos Lineales , Masculino , Mastocitos/enzimología , Mastocitos/patología , Índice de Severidad de la Enfermedad , Ultrasonografía Doppler , Valina/administración & dosificación , ValsartánRESUMEN
A 55-years-old man was admitted to our hospital with a 6-month history of general fatigue, purulent nasal discharge, polyuria, and polydipsia. Endocrinological findings revealed central diabetes insipidus (CDI) with mild anterior pituitary dysfunction. Imaging studies revealed thickening of the proximal end of the pituitary stalk just below the third ventricle, a mass in the paranasal sinus, and a mass encompassing the abdominal aorta. Histopathology of the mass in the paranasal sinus revealed abundant IgG4-positive plasma cells, and the IgG4 serum level was markedly elevated. Thus, he was diagnosed with IgG4-related multifocal fibrosclerosis. Therapy with prednisolone resulted in complete resolution of clinical symptoms and reduction in size of the masses in the affected organs. However, CDI remained unchanged. This is the first case in which the cause of CDI was IgG4-related multifocal fibrosclerosis. IgG4-related sclerosing disease should be included in the differential diagnosis of thickening of the pituitary stalk with CDI, and a search for extra-pituitary involvement is essential.
Asunto(s)
Aorta Abdominal/patología , Diabetes Insípida/complicaciones , Inmunoglobulina G/sangre , Senos Paranasales/patología , Hipófisis/patología , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , EsclerosisRESUMEN
Chymase degrades angiotensin I (AI) to form angiotensin II (AII), probably constituting a bypass of the renin-angiotensin cascade. Chymase activity increases in some vascular diseases. In the kidney, an increase in chymase activity was reported in an animal model of ischemic kidney of renovascular hypertension (RVH); however, no such evidence has been provided in humans. We treated a 64-year-old patient with severe unilateral RVH and atherosclerosis, for whom removal of the ischemic kidney was the only option. Using immunohistochemical staining, we investigated chymase activity in the removed kidney and associated artery and vein. An increase in chymase activity, together with mast cells infiltrating the interstitium, was observed where interstitial fibrosis was seen. In the renal artery, where severe atherosclerosis was seen, and also in the vein, mast cell infiltration in the adventitia was accompanied by chymase. The captopril test showed an increase in serum aldosterone level, with a concomitant increase in plasma renin activity and decrease in blood pressure. Because the decrease in blood pressure implies a decrease in circulatory AII levels, it is plausible that in this patient, chymase had a role in AII formation in the adrenal gland to stimulate aldosterone secretion. Thus, by means of captopril, AI levels increased, and chymase may have produced AII in loci tissues, which, in turn, stimulated aldosterone secretion. This is the first report of an increase in chymase activity in the interstitium of an ischemic kidney and renal artery and vein in a patient with RVH and atherosclerosis.
Asunto(s)
Angiotensina II/biosíntesis , Arteriosclerosis/complicaciones , Hipertensión Renovascular/patología , Isquemia/patología , Riñón/irrigación sanguínea , Mastocitos/enzimología , Obstrucción de la Arteria Renal/complicaciones , Serina Endopeptidasas/análisis , Angiografía de Substracción Digital , Angiotensina I/metabolismo , Arteriosclerosis/enzimología , Captopril , Quimasas , Femenino , Humanos , Hiperaldosteronismo/inducido químicamente , Hipertensión Renovascular/diagnóstico por imagen , Hipertensión Renovascular/enzimología , Hipertensión Renovascular/etiología , Hipertensión Renovascular/cirugía , Isquemia/complicaciones , Isquemia/cirugía , Riñón/enzimología , Riñón/patología , Riñón/cirugía , Persona de Mediana Edad , Nefrectomía , Arteria Renal/enzimología , Obstrucción de la Arteria Renal/enzimología , Venas Renales/enzimología , Renina/sangre , Sistema Renina-Angiotensina/fisiología , Serina Endopeptidasas/fisiología , FumarRESUMEN
Experimental studies suggest that some long-acting calcium antagonists decrease glomerular hypertension and suppress the progression of nephropathy, but clinical evidence is lacking. To investigate clinically whether a long-acting calcium antagonist, benidipine, lowers glomerular capillary hydraulic pressure via a decrease in efferent arteriolar resistance and decreases proteinuria, we examined hypertensive patients with nondiabetic nephropathy. The subjects were 7 patients with chronic glomerulonephritis or glomerulosclerosis. Before and during the administration of benidipine (4 mg/day), systemic pressure, glomerular hemodynamics, the sodium sensitivity index (reciprocal of the pressure-natriuresis curve), and urinary excretion of proteins (total protein, albumin, and immunoglobulin G) were investigated. The glomerular hemodynamics in terms of glomerular capillary hydraulic pressure and resistance of afferent and efferent arterioles were calculated from the renal clearance, plasma total protein concentration, and pressure-natriuresis relationship. Benidipine lowered the mean arterial pressure from 105 +/-5 to 99 +/- 4 mm Hg (p = 0.002; mean +/- SD) and glomerular pressure from 48 +/- 8 to 39 +/- 5 mmHg (p = 0.006) by decreasing the resistance of efferent arterioles. Benidipine made the pressure-natriuresis curve steeper and decreased the median sodium sensitivity index from 0.099 (0.084 and 0.117; 25th and 75th percentiles) to 0.048 (0.017 and 0.058; p = 0.018). Urinary excretion of proteins did not change. Our clinical study showed that benidipine lowered the glomerular pressure by decreasing the resistance of efferent arterioles and decreased the sodium sensitivity of blood pressure, but did not affect proteinuria in patients with nondiabetic nephropathy.