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BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.
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Ensayos Clínicos como Asunto , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Riñón/metabolismo , Adulto , Consenso , Técnica Delphi , Enfermedad de Fabry/genética , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/patología , Femenino , Globósidos/uso terapéutico , Glucolípidos/uso terapéutico , Humanos , Isoenzimas/genética , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Persona de Mediana Edad , Calidad de Vida , Esfingolípidos/uso terapéutico , Resultado del Tratamiento , Trihexosilceramidas/uso terapéutico , alfa-Galactosidasa/genéticaRESUMEN
Objective To evaluate long-term mortality and end-stage renal disease (ESRD) in a cohort of Norwegian patients with biopsy-proven lupus nephritis (LN). Methods Renal biopsies were obtained from 178 patients with LN from 1988 until 2007. Mortality rate and death causes were provided by Statistics Norway and ESRD data were provided by the Norwegian Renal Registry. Risk factors for all-cause mortality were evaluated by Cox regression. Standardized mortality ratio (SMR) was compared to observed deaths in a matched general population sample. Results Mean age was 37.6 (±14.4) years, and median time of follow-up was 8.5 years (0-26.2). Thirty-six patients (20.2%) died during follow-up. The SMR for all-cause mortality was 5.6 (Confidence interval [CI] 3.7-7.5). In an adjusted multivariate analysis proliferative glomerulonephritis (LN class IV) was independently associated with all-cause mortality; hazard ratio (HR) 2.6 (Confidence interval [CI] 1.2-5.7 p = 0.017). Main causes of death were infections (47.2%) and cardiovascular events 8 (22.2%). Thirty-six patients (20.2%) reached ESRD. Conclusions Biopsy-proven LN is associated with increased mortality compared to the general population. LN class IV is associated with all-cause mortality. Infections and cardiovascular events were the most common causes of death. Patients with LN have a high incidence of ESRD.
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Glomerulonefritis/epidemiología , Fallo Renal Crónico/epidemiología , Nefritis Lúpica/fisiopatología , Adulto , Biopsia , Causas de Muerte , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Glomerulonefritis/etiología , Glomerulonefritis/mortalidad , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Nefritis Lúpica/complicaciones , Nefritis Lúpica/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Noruega/epidemiología , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
AIMS: The renal prognosis in Fabry disease is better when enzyme replacement therapy (ERT) is initiated before glomerular filtration rate (GFR) deteriorates. Current studies evaluating kidney function in Fabry disease are mainly based on the MDRD equation. The aim of this cross sectional study was to compare estimated and measured GFR in adult Fabry patients with normal or near normal kidney function. METHODS: Iohexol GFR (mGFR) was compared to estimated GFR (eGFR) (MDRD, Cockcroft-Gault and Counahan-Barratt equations) in 8 male and 13 female Fabry patients with minimal albuminuria and mean mGFR of 94 ml/min/1.73 m2 for both genders. RESULTS: A significant overestimation of eGFR-MDRD by 24 ml/min/1.73 m2 was seen in male Fabry patients. The performance of the MDRD equation was similar to mGFR in female Fabry patients. GFR was significantly overestimated by the Cockcroft-Gault equation, whilst Counahan-Barratt equation gave results in agreement with mGFR for both male and female Fabry patients. CONCLUSIONS: Overestimation of eGFR-MDRD in Fabry patients with CKD stage 1 - 2 and minimal albuminuria may prevent recognition of early progressive renal failure and delayed ERT initiation may be the consequence. Exact GFR markers should be part of the routine evaluation of GFR in Fabry patients.
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Enfermedad de Fabry/fisiopatología , Tasa de Filtración Glomerular/fisiología , Insuficiencia Renal/fisiopatología , Adolescente , Adulto , Estudios de Casos y Controles , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Pruebas de Función Renal , Modelos Lineales , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Estudios RetrospectivosRESUMEN
Essentials Prolonged activated partial thromboplastin times (APTT) were found in drug users with renal failure. An oral methadone solution containing polyvinylpyrrolidone (PVP) had been injected intravenously. Spiking normal plasma with increasing concentrations of PVP resulted in artifically prolonged APTT. APTT prolongation may indicate PVP deposits as underlying cause in patients with renal failure. SUMMARY: Unexpectedly prolonged activated partial thromboplastin times (APTTs) were noted in several patients with chronic renal insufficiency and a history of intravenous drug abuse. Deposits of polyvinylpyrrolidone (PVP), an excipient in one oral methadone solution used in opioid maintenance programs, were found in renal biopsies. One case is described in detail, and this is followed by a summary of findings in 11 other patients and the results of an in vitro experiment in which plasma was spiked with PVP at increasing concentrations. APTTs measured with STA PTT automate (Stago) were prolonged in all patients and in spiked samples, whereas supplemental coagulation parameters and APTTs measured with HemosIL SynthAsil or Actin FSL (Siemens) were within reference intervals. These results indicate that interference with APTTs by PVP is reagent-dependent. We suggest that a prolonged APTT should raise the suspicion of PVP deposit-associated kidney disease in patients with chronic renal failure and a history of intravenous drug abuse.
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A wide spectrum of acute or chronic heart failure and thromboembolic events may be causally related to high-grade uni- or bilateral renovascular hypertensive disease, and the variety of these potential interactions may be unrecognized in clinical practice. We present three cases that illustrate the clinical variability of cardiorenal failure and thromboembolic events seen in patients with significant renal artery stenoses. These are high-risk patients where severe morbidity and mortality are threatening. Our patients also demonstrate that the diagnosis often is delayed, and that recanalizing of occluded renal arteries may be highly cost-effective and life-saving in such patients.
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Insuficiencia Cardíaca/etiología , Obstrucción de la Arteria Renal/complicaciones , Insuficiencia Renal/etiología , Tromboembolia/etiología , Anciano , Angiografía , Resultado Fatal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obstrucción de la Arteria Renal/diagnóstico por imagen , Factores de RiesgoRESUMEN
We describe a man and a woman with Fabry's disease. Renal biopsies showed late and early stages respectively of focal and segmental glomerulosclerosis (FSGS) and vascular changes. Clinically the hemizygous patient had advanced renal disease with nephrotic range proteinuria and serum creatinine 122 micromol/l. The female carrier had minimal albuminuria, borderline GFR with a normal serum creatinine, acroparesthesias, moderate fatigue, tinnitus and headache accompanied by ischemic cerebral lesions. Enzyme replacement therapy (ERT) was initiated according to our Fabry protocol, partly due to the renal morphologic findings. We conclude that FSGS and vascular changes may be an early morphologic finding in Fabry's disease, even in patients with subtle albuminuria. The potential role of FSGS as a marker of progressive renal disease in some Fabry patients is discussed. As FSGS and vascular changes obviously may exist across a wide range of clinical presentations and have potential prognostic implications, we suggest that a renal biopsy should be performed prior to enzyme replacement therapy in all adult Fabry patients with proteinuria of various levels. Efforts should be made to develop a scoring system to evaluate potential histologic markers. Protocol biopsies may have therapeutic implications and may provide valuable information in the evaluation of start and dosing of ERT.
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Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/patología , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomeruloesclerosis Focal y Segmentaria/patología , Biopsia con Aguja , Enfermedad de Fabry/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Humanos , Inmunohistoquímica , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Prednisolona/uso terapéutico , Pronóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The effect of doxazosin versus captopril on blood pressure, albuminuria, and left ventricular mass was studied in 33 hypertensive type-1 diabetic patients randomized to 6 months treatment with captopril (17 patients, mean daily dose 100 mg) or doxazosin (16 patients, mean daily dose 9 mg). Casual and 24-h ambulatory blood pressure (24hBP) were reduced from 163/95 to 144/83 mm Hg and 152/86 to 145/81 mm Hg, respectively, in the captopril group, and from 160/93 to 145/86 mm Hg and 156/86 to 147/79 mm Hg in the doxazosin group (all P < .05). The achieved 24hBP on treatment was positively associated with pretreatment levels of glycosylated hemoglobin (HbA1c) and plasma atrial natriuretic peptide (r = 0.53 and 0.59, respectively, both P < .01). Albuminuria did not change significantly in either group. Left ventricular hypertrophy was present in 13 patients (7 in the captopril and 6 in the doxazosin group). Left ventricular mass was reduced by an average of 27% and 23%, respectively, in these patients (both P < .01), but did not change significantly in patients without left ventricular hypertrophy. The reduction in left ventricular mass was positively associated with the presence of baseline left ventricular hypertrophy and inversely with dietary sodium intake and achieved casual blood pressure on treatment (R2 = 0.59, P < .001). We conclude that doxazosin and captopril used for 6 months are equally effective in reducing blood pressure and left ventricular hypertrophy in hypertensive type-1 diabetic patients; the antihypertensive effect is closely related to glycemic control; and dietary sodium intake and achieved casual blood pressure after treatment are independent determinants of the reduction in left ventricular mass seen in these patients.
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Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Captopril/uso terapéutico , Diabetes Mellitus Tipo 1/complicaciones , Doxazosina/uso terapéutico , Ecocardiografía , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Adulto , Albuminuria/orina , Femenino , Ventrículos Cardíacos , Humanos , Hipertensión/diagnóstico por imagen , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
A descriptive survey of renal hemodynamics in the major experimental models of progressive renal disorders (primary loss of renal tissue, primary glomerular injury and primary hypertension) is given. Although the pathogenesis in the different models differs in several respects, increases in glomerular capillary pressure and renal growth factors are important for the development of progressive renal disorders. In primary glomerular disorders, interstitial immune reactions seem to be critical. In glomerular nephritis with increased capillary wall thickness, the increase in glomerular capillary pressure may be of less importance than in other models. A third important factor for progression of renal disorders is a gradual breakdown of autoregulation of renal blood flow and glomerular filtration rate exposing the glomerulus to the variations in systemic blood pressure.
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Fallo Renal Crónico/fisiopatología , Animales , Modelos Animales de Enfermedad , Sustancias de Crecimiento/fisiología , Hipertensión Renovascular/etiología , Fallo Renal Crónico/etiología , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/fisiopatología , Circulación Renal/fisiologíaRESUMEN
This report shows our experience with 13 patients aged 70-83 years who started CAPD treatment 1981-1989. There were 7 females and 6 males. The total treatment time was 298 months (range 4-104). Nine of the patients were able to perform all CAPD procedures while 4 patients needed some help. The patients who were able to take care of all procedures had the lowest period of terminal care, i.e. the period preceding death when the patients had to be taken care of by the hospital staff. The terminal care period was 5.1% of the total treatment period. In the patients who needed help from the beginning of the treatment, the terminal care was 17.2% of the total treatment period. The frequency of peritonitis was 1 per 10.2 treatment month. The main cause for hospitalization was peritonitis and terminal care at the end of the lives of the patients. No patients died due to peritonitis. However, two patients were transferred to hemodialysis due to recurrent peritonitis and ultrafiltration loss, one was transplanted and one was transferred to IPD due to weakness. The causes of death were myocardial infarction, cerebral stroke and cardiac insufficiency. No deaths were due to peritonitis. CAPD in patients above 70 years of age is acceptable both on the basis of the somatic situation and of quality of life.
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Diálisis Peritoneal Ambulatoria Continua , Actividades Cotidianas , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Hospitalización , Humanos , Fallo Renal Crónico/terapia , Masculino , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Peritonitis/etiologíaRESUMEN
UNLABELLED: Sufficient nutritional intake is important to adjust the increased catabolic rate in uremic patients during dialysis treatment. Increased glucose absorption during PD treatment may, however, interfere with the amount of muscle- and fat-mass in the body. We have therefore studied the amount of total body fat composition in 8 male PD patients (treatment period 79 months, range 3-23 before and 165.5 months, range 8-35.5 after the study). Food intake was recorded for 7 days twice in four patients with an interval of 6-8 months. Total body fat (%) was measured by means of a computerized model of near infrared interactance (IRI) ("FUTREX") on the dominant upper arm. The energy and protein intake were 1731 +/- 292 kcal. and 86.9 +/- 17.2 g (n = 4) during the first recording period of food intake. In the second period the energy and protein intake were 1676 +/- 105 kcal and 72.7 +/- 10.2 g (n = 4) (NS). The total body fat increased from 19.8 +/- 2.9 to 22.5 +/- 3.0 (p < 0.05), in spite of unchanged total body weight. CONCLUSION: PD patients seem to accumulate fat during PD treatment with glucose as osmotic agent. This may influence the cardiovascular risks. The results indicate nutritional adjustments and possibly also increased physical activity.
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Tejido Adiposo , Composición Corporal , Diálisis Peritoneal , Adulto , Anciano , Peso Corporal , Soluciones para Diálisis , Proteínas en la Dieta/administración & dosificación , Ingestión de Energía , Glucosa/administración & dosificación , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Lípidos/sangre , Masculino , Persona de Mediana Edad , Diálisis Peritoneal Ambulatoria Continua , Albúmina Sérica/análisisRESUMEN
BACKGROUND/AIMS: Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations in the calcium- sensing receptor (CASR). We aimed to describe the phenotypic variation within a large family with ADH, especially kidney and cerebral basal ganglia calcifications. METHODS: Fifteen related subjects carrying the CASR mutation T151M participated in a cross-sectional study of calcium homeostasis, renal ultrasonography, cerebral CT, bone mineral density, and health-related quality of life (HRQoL). RESULTS: Eight subjects had received vitamin D treatment (mean duration 15.3 years; range 11-20 years). Urinary calcium excretion was elevated in 5/8 vitamin-D-treated and in 3/7 untreated subjects. Serum magnesium, calcium and parathyroid hormone remained at the lower reference limit or below. Renal calcifications were found in 12 of 14 (86%) and basal ganglia calcifications in 5 of 11 (46%) subjects, independently of vitamin D therapy. The glomerular filtration rate was moderately reduced in 3 subjects. Mean bone mineral density and bone markers were normal. HRQoL was impaired in the vitamin-D-treated group despite correction of the hypocalcaemia. CONCLUSIONS: The impact of the CASR mutation on calcium homeostasis varied greatly. Kidney and basal ganglia calcifications are common in ADH independently of vitamin D treatment, which, however, increases urinary calcium excretion and may promote urolithiasis.
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Hipocalcemia/genética , Receptores Sensibles al Calcio/metabolismo , Adolescente , Adulto , Anciano , Densidad Ósea/genética , Calcinosis/genética , Calcio/metabolismo , Calcio/orina , Cerebro/metabolismo , Cerebro/patología , Estudios Transversales , Femenino , Humanos , Hipocalcemia/metabolismo , Hipocalcemia/patología , Hipocalcemia/orina , Riñón/diagnóstico por imagen , Riñón/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , Mutación , Hormona Paratiroidea/sangre , Linaje , Fenotipo , Receptores Sensibles al Calcio/genética , Análisis de Secuencia de ADN , Estadísticas no Paramétricas , Ultrasonografía , Adulto JovenRESUMEN
Stimulation of the renin angiotensin system, catecholamines and antidiuretic hormone causes prominent vasoconstriction in severe heart failure. Angiotensin converting enzyme inhibitors reverse these effects, and thus ameliorate cardiac function and reduce mortality in severe heart failure. Angiotensin II is an important regulator of renal function in diseases with renal hypoperfusion, and treatment with angiotensin converting enzyme inhibitors may cause a serious decrease in glomerular filtration and hyperkalemia. Asymptomatic heart failure, acute heart failure and acute myocardial infarction are areas where angiotensin converting enzyme inhibitors may prove beneficial in the future.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Resistencia Vascular/efectos de los fármacosRESUMEN
Malnutrition and low serum albumin values predict increased mortality in uremic patients. Infrared interactance represents a novel approach to the estimation of body composition. We have examined total body fat, body water and fat-free weight in our male haemodialysis (n = 24) and peritoneal dialysis (n = 17) patients. There were no differences between the groups in a cross-sectional study. A longitudinal study showed a significant increase of total body fat (%) in the peritoneal dialysis patients after five months (mean values +/- SEM) (from 19.8 +/- 2.3 to 22.6 +/- 2.4, p < 0.05), and a significant decrease of body water (%) (from 59.9 +/- 1.5 to 58.2 +/- 1.6, p < 0.05). The difference in total body fat between the haemodialysis (n = 14) and peritoneal dialysis (n = 10) groups reached statistical significance (16.5 +/- 1.7 versus 22.6 +/- 2.4, p < 0.05). No difference was found in serum albumin. Infrared interactance has the capacity to characterize time-dependent differential changes of body composition in various dialysis modalities. Further studies are needed to describe the validity of the method for identification of patients with increasing malnutrition.
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Composición Corporal , Índice de Masa Corporal , Diálisis Peritoneal/efectos adversos , Diálisis Renal/efectos adversos , Espectrofotometría Infrarroja/instrumentación , Anciano , Estudios Transversales , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Evaluación Nutricional , Trastornos Nutricionales/diagnóstico , Trastornos Nutricionales/epidemiología , Trastornos Nutricionales/etiologíaRESUMEN
Malnutrition, shown by fat depletion and muscle wasting, is common in uremia. The methods used to describe body composition in uremia are controversial. We have used ultrasonography of the thigh to evaluate fat and muscle in haemodialysis patients (group 1) (n = 14), peritoneal dialysis patients (group 2) (n = 10) and normal controls (group 3) (n = 13). Musculus rectus femoris diameter (0.84 +/- 0.06 cm versus 1.15 +/- 0.08 cm, p < 0.05) and cross sectional area (3.0 +/- 0.4 cm2 versus 5.5 +/- 0.4 cm2, p < 0.01) were significantly reduced in group 1 compared with group 3, as was also muscle area in group 2 (3.9 +/- 0.6, p < 0.05), indicating malnutrition in the dialysis patients. Peritoneal dialysis patients tended to have more subcutaneous fat (p = 0.07) and a larger musculus rectus diameter (p = 0.09) than haemodialysis patients, possibly reflecting better preserved nutritional status. Ultrasonography was equal to computed tomography for estimating these parameters. Ultrasonography is a useful tool for evaluating body composition in uremia, and has a capacity for detection of malnutrition, and possibly for early discrimination between patient groups with different dialysis modalities.
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Tejido Adiposo/diagnóstico por imagen , Composición Corporal , Músculos/diagnóstico por imagen , Diálisis Peritoneal/efectos adversos , Diálisis Renal/efectos adversos , Tejido Adiposo/patología , Anciano , Estudios Transversales , Humanos , Masculino , Persona de Mediana Edad , Músculos/patología , Noruega/epidemiología , Evaluación Nutricional , Trastornos Nutricionales/diagnóstico por imagen , Trastornos Nutricionales/epidemiología , Trastornos Nutricionales/etiología , UltrasonografíaRESUMEN
Three case histories are described which highlight some of the predisposing risk factors and therapeutic strategies in the event of acute severe renal failure during treatment with ACEI. With appropriate therapy, renal function is usually restored within a few days. Renal artery stenosis, dehydration and diuretics stimulate the renin angiotensin system and make preservation of normal renal function, increasingly dependent on angiotensin II. The prevalence of renal artery stenosis is substantially increased in patients with peripheral vascular disease or with coronary artery disease with concomitant hypertension. Patients should be told about the increased risk of adverse effects to the kidneys if they become dehydrated. In these cases it is essential to reduce the dose diuretics and ACEI, and it may be necessary to give parenteral fluid substitution.
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Lesión Renal Aguda/inducido químicamente , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Diuréticos/administración & dosificación , Diuréticos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
This article presents the clinical and radiological findings in three patients with acute obstructive renal failure. In a setting of typical clinical symptoms of acute postrenal obstruction, the lack of or only minimal ultrasonographic dilatation of the pelvicalyceal system should not lead to the conclusion that there is no obstruction until supplementary invasive procedures have demonstrated open urinary tracts. Minimal pelvic dilatation in acute obstructive renal failure is typically associated with malignant diseases encasing the distal parts of the ureters, retroperitoneal fibrosis, urinary calculi and urinary infections. Various pathophysiologic mechanisms are discussed.
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Lesión Renal Aguda/diagnóstico , Pelvis Renal/fisiopatología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Adulto , Anciano , Dilatación Patológica/complicaciones , Dilatación Patológica/diagnóstico , Dilatación Patológica/fisiopatología , Humanos , Cálculos Renales/complicaciones , Cálculos Renales/diagnóstico , Cálculos Renales/fisiopatología , Pelvis Renal/diagnóstico por imagen , Masculino , Radiografía , Ultrasonografía , Cálculos Ureterales/complicaciones , Cálculos Ureterales/diagnóstico , Cálculos Ureterales/fisiopatología , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/diagnóstico , Obstrucción Ureteral/fisiopatologíaRESUMEN
OBJECTIVE: The renal functional consequences of an activated sympathetic nervous system and plasma atrial natriuretic hormone (ANP) in various renal diseases are not well described. We hypothesize that norepinephrine (NE) and ANP have antagonizing effects on renal hemodynamics in diseased kidneys. MATERIAL AND METHODS: Plasma NE, ANP. glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and mean arterial pressure (MAP) were measured in the upright position in healthy controls (n = 9) and hypertensive patients with reduced GFR (n =11). The same parameters were compared between healthy controls (n = 6) and hypertensive patients with reduced GFR (n = 6) in upright and supine positions. RESULTS: Upright plasma NE and ANP were significantly elevated in the patients compared with the controls (4.4 +/- 0.4 vs 2.1 +/- 0.2 nmol/l (p < 0.001) and 1.3.5 +/- 2.1 vs 6.9 +/- 1.0 nmol/l (p < 0.01) respectively). With change from upright to supine position plasma NE decreased in the controls (2.2 +/- 0.3 vs 1.7 +/- 0.3 nmol/l) (p < 0.01) and patients (3.8 +/- 0.4 vs 2.6 +/- 0.4) (p < 0.01). Supine ANP increased in controls (5.5 +/- 1.0 vs 8.3 +/- 1.1) (p < 0.01) but not in patients (14.3 +/- 3.8 vs 16.1 +/- 3.8 nmol/l) (p > 0.10). Plasma NE correlated positively with MAP (p < 0.001) and negatively with GFR (p < 0.01) in the upright but not supine position. A positive correlation between NE and ANP was observed in upright (p < 0.001) but not in supine position. ANP correlated negatively with GFR in the upright (p < 0.01) but not supine position. No position dependent changes were seen in GFR and ERPF, but supine filtration fraction (FF) increased insignificantly in the patient group (0.23 +/- 0.02 vs 0.24 +/- 0.02) (p < 0.05). CONCLUSION: Hypertensive patients with reduced GFR have elevated levels of plasma NE and ANP in the upright body position. When the upright and supine positions are compared, plasma NE declines in the supine position in controls and hypertensive renal failure patients. and plasma ANP levels are elevated only in the upright position in hypertensive renal failure patients where the sympathetic nervous system is activated. A significant positive relationship between plasma NE and ANP was observed only in the upright position. The upright body position seems superior to recumbency in the characterization of these hormonal changes in hypertensive chronic renal failure patients.
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Hipertensión/fisiopatología , Fallo Renal Crónico/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Factor Natriurético Atrial/sangre , Presión Sanguínea , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Postura , Flujo Plasmático Renal Efectivo , Simpatomiméticos/sangreRESUMEN
OBJECTIVE: Increased physical activity is followed by a stimulation of the sympathetic nervous system and this effect is probably more pronounced in patients with chronic renal failure and hypertension than in healthy controls. The role of sustained exercise in hypertensive patients with chronic renal failure, with and without antihypertensive therapy, is unclear, as is hormonal regulation of the renal hemodynamics. We hypothesized that prolonged low-intensity bicycle exercise would have a greater effect in patients with chronic renal failure than in controls, and that antihypertensive treatment would ameliorate these effects. MATERIAL AND METHODS: Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), mean arterial blood pressure (MAP), norepinephrine (NE) and atrial natriuretic peptide (ANP) were measured in the upright position before and during low-intensity exercise for 2 h in healthy controls (n = 8) and in hypertensive patients with moderately reduced renal function who were not taking antihypertensives (n = 7) or who were receiving treatment with captopril (n = 10), enalapril (n = 6) or verapamil (n = 9). RESULTS: GFR tended to decrease and ERPF decreased significantly in healthy individuals when exercise duration was prolonged from 1 to 2 h. An earlier decline in GFR and ERPF was seen in the renal failure patients compared with the controls. Filtration fraction (FF) increased during exercise in all groups except the group taking enalapril. MAP increased in the captopril group during exercise but was unchanged in the other groups. Treatment with captopril produced a more pronounced and earlier fall in exercise-induced GFR than in untreated controls, while verapamil treatment completely blunted the decline in GFR, with a concomitant increase in plasma ANP. No significant changes were seen in plasma NE levels, but urinary NE excretion increased in controls and captopril-treated patients during exercise. CONCLUSIONS: The results suggest that prolonged low-intensity exercise has a substantially greater effect on renal hemodynamics in hypertensive renal failure patients than in healthy controls, with negligible changes in plasma NE levels. Verapamil treatment seems to ameliorate the renal effects of exercise on GFR in these patients, and this may in part be mediated via a stimulatory effect on ANP.
Asunto(s)
Ejercicio Físico , Hemodinámica/fisiología , Hipertensión/terapia , Fallo Renal Crónico/terapia , Circulación Renal/fisiología , Adulto , Antihipertensivos/uso terapéutico , Factor Natriurético Atrial/sangre , Presión Sanguínea/fisiología , Captopril/uso terapéutico , Enalapril/uso terapéutico , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Flujo Plasmático Renal Efectivo/fisiología , Verapamilo/uso terapéuticoRESUMEN
We describe a standardized clearance method over 5 h (one hour equilibration followed by eight consecutive 30 min clearance periods [period 2-9]) for the estimation of GFR (iothalamate I125) and ERPF (hippuran I131) during water diuresis in ambulatory and exercising patients. Four groups were examined. In group I (normal controls, n = 15) there were no significant changes in GFR, ERPF and FF (P > 0.10) during repeated clearance periods (mean of period 2-5 versus period 6-9). The reproducibility of the method was studied at a mean interval of 3.7 weeks in a group of patients with stable reduction of GFR (group II, n = 7). The values for GFR, ERPF, FF and RVR did not change significantly in this group, and correlated significantly between repeated studies (r = 0.81 to r = 0.99). In group III (untreated hypertensive patients with reduced GFR, n = 13) there was a time dependent 7.2% decrease in GFR (P < 0.05), significantly different from group I (P < 0.02), a 10.0% decrease in ERPF (P < 0.01) and no significant change in FF (P = 0.08) when the mean of period 2-5 was compared with the mean of period 6-9. In healthy controls (group IV, n = 8) light sustained bicycle exercise (25 W) induced a 7.1% decline in GFR (P < 0.01), 17.4% decline in ERPF (P < 0.001) and a 13.6% increase in FF (P < 0.001). We conclude that ambulatory measurements of GFR and RPF can be carried out over a period of 5 h with satisfactory precision and repeatability. Ambulatory hypertensive patients with moderately reduced GFR showed the same degree of time dependent downward drift of GFR and ERPF without exercise as was seen in healthy individuals during light exercise. Accordingly, in these groups single clearance periods imply a risk for under or overestimation of renal function, and time controls are necessary during clearance studies.