RESUMEN
OBJECTIVE: The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials. METHODS: Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the Liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments. RESULTS: People with type 2 diabetes were prepared to pay an extra 2.64/day for liraglutide compared with rosiglitazone, an extra 1.94/day compared with glimepiride, an extra 3.36/day compared with insulin glargine, and an extra 0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators. CONCLUSIONS: WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone, glimepiride, and insulin glargine, and administration frequency compared with exenatide.
Asunto(s)
Costo de Enfermedad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/economía , Péptido 1 Similar al Glucagón/análogos & derivados , Hipoglucemiantes/economía , Hipoglucemiantes/uso terapéutico , Incretinas/uso terapéutico , Análisis Costo-Beneficio , Manejo de la Enfermedad , Exenatida , Péptido 1 Similar al Glucagón/economía , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Incretinas/economía , Insulina Glargina , Insulina de Acción Prolongada/economía , Insulina de Acción Prolongada/uso terapéutico , Liraglutida , Péptidos/economía , Péptidos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Rosiglitazona , Compuestos de Sulfonilurea/economía , Compuestos de Sulfonilurea/uso terapéutico , Tiazolidinedionas/economía , Tiazolidinedionas/uso terapéutico , Ponzoñas/economía , Ponzoñas/uso terapéutico , Pérdida de PesoRESUMEN
OBJECTIVES: This study aimed to investigate the most important consequences of diabetes medication, as measured by the patients' willingness to pay (WTP). RESEARCH DESIGN AND METHODS: People in Sweden were recruited using existing nationwide e-mail panels if they were adults (>or=18 years) with type 2 diabetes and were receiving pharmacological anti-diabetes treatment(s). Data were collected electronically and results were analysed using a standard statistical model designed for choice games (conditional logit). Six characteristics relating to treatment of diabetes were examined: weight (gain or loss), mean glycated haemoglobin level (HbA(1c)), hypoglycaemic events, nausea, need for injections (with or independently of meals), and blood glucose testing. RESULTS: A total of 461 people with type 2 diabetes (291 males; 170 females) completed an internet questionnaire and were eligible for inclusion. Participants placed high value on weight loss and nausea avoidance; they would pay 176 Swedish Krona (SEK)/euro15.61 per month to lose 1 kg, and would pay SEK 560 (euro49.67) per month to avoid nausea completely. Patients wanting to reduce the number of hypoglycaemic events from three per month to none were willing to pay SEK 419 (euro37.17) per month. Patients valued a 1 percentage point reduction in HbA(1c) at SEK 414 (euro36.72) per month. Participants preferred taking tablets to injections and required a compensation of SEK 376 (euro33.35) to accept one injection/day. Injections independent of meals were preferred to injections with meals (WTP: SEK 140/euro12.42 per month). Potential limitations of this study are that the preferences expressed may not match preferences in real-life situations, and bias through the use of electronic questionnaire, which restricted participation to those with access to, and experience with, the internet. CONCLUSION: People with type 2 diabetes were willing to pay a considerable amount of money each month to lose weight, reduce or avoid hypoglycaemic events and reduce HbA(1C).
Asunto(s)
Diabetes Mellitus Tipo 2/terapia , Financiación Personal , Cooperación del Paciente , Prioridad del Paciente , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Peso Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/economía , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/economía , Inyecciones/métodos , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Modelos Econométricos , Náusea/prevención & control , SueciaRESUMEN
AIMS: To study the occurrence of heart disease and death in Type 1 diabetic patients and evaluate whether presence of microangiopathy, i.e. nephropathy and retinopathy, was associated with the outcome. METHODS: A 12-year observation study of 462 Type 1 diabetic patients without a previous history of heart disease at baseline who were treated under routine care in a hospital out-patient clinic. RESULTS: A total of 85 patients developed signs of heart disease, i.e. myocardial infarction (n = 41), angina (n = 23), and heart failure (n = 17) and 56 patients died. The mortality for patients without signs of heart disease during the observation period was 7.6% compared with 51% in patients with myocardial infarction (P < 0.001), 26% in patients with angina (P < 0.01) and 65% in patients with heart failure (P < 0.001). The relative risk for death was 9.0 (P < 0.001) and 2.5 (P < 0.05) times higher in patients with macroalbuminuria and microalbuminuria, respectively. The risk for cardiovascular death was 18.3 times (P < 0.001) higher in patients with macroalbuminuria compared with patients with normoalbuminuria. In patients with sight-threatening retinopathy, the relative risk for death was 7.0 times higher (P < 0.01) and the risk for coronary heart disease events 4.4 times higher (P < 0.05) compared with patients with no retinopathy. However, when retinopathy was adjusted for presence of macroalbuminuria, this association disappeared. CONCLUSION: This study shows a high incidence of heart disease in patients with Type 1 diabetes. The worse prognosis was seen in patients with sight-threatening retinopathy and macroalbuminuria and microalbuminuria at baseline. Macroalbuminuria and microalbuminuria were independently associated with a high risk for heart disease and death while the association with sight-threatening retinopathy only occurred in the presence of nephropathy.
Asunto(s)
Albuminuria/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/etiología , Nefropatías Diabéticas/complicaciones , Retinopatía Diabética/complicaciones , Cardiopatías/etiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
UNLABELLED: Renal function in proteinuric glomerular diseases correlates to the changes in urine IgM but not to the changes in the degree of albuminuria. BACKGROUND: Albuminuria is believed to correlate to the progression of renal failure in glomerular diseases. Nevertheless, many patients with glomerular disorders maintain their renal function despite persistent albuminuria. In previous studies, we found that the baseline urine excretion of IgM, rather than the degree of albuminuria, predicts the renal outcome in glomerulopathies. In the present study, we examine correlations between changes in the content and in the amount of urine proteins and renal survival during a follow-up time of 3.5 years. METHODS: An observational study of a mean of 44 (+/- 3.6) months was conducted in 37 proteinuric patients (21 males and 16 females) with biopsy-verified primary glomerular disease. The patients were subdivided, according to the findings at the end of the study, into 3 groups, 1 group with decreasing albuminuria (by more than 50%), 1 group with persisting albuminuria and low (< 0.04 mg/mmol creatinine) urinary IgM excretion and 1 group with persisting albuminuria and with high (> or = 0.04 mg/mmol) urinary IgM excretion. RESULTS: All patients that showed remission of albuminuria had also low IgM excretion at the end of the study. All these patients, except 1, maintained their renal function. Patients with persistent albuminuria and high urinary IgM excretion showed a decrease in the glomerular filtration rate (GFR) of a mean of 9.6 ml/min/year compared to a mean GFR increase by 1.5 ml/min/year in patients with low IgM excretion and the same degree of albuminuria (p < 0.01). Seven out of the 9 patients in the former group fall in GFR by more than 5 ml/min/year compared to only 1 of the 10 patients in the latter group. Furthermore, the GFR alterations that occurred during follow-up time correlated in a higher degree to the changes in urinary IgM excretion (r = 0.6, p < 0.01) than to the changes in the degree of albuminuria, (r = 0.4, p < 0.05). A stepwise regression analysis indicated that increased urine IgM excretion is a strong predictor of the GFR decline (r = 0.73, p < 0.001). CONCLUSION: High urinary IgM excretion correlates to decreased GFR in primary glomerular diseases regardless of the degree of albuminuria. In parallel, low urinary IgM excretion indicates beneficial prognosis in these diseases. Since IgM passes the glomerular barrier entirely through large shunts or defects in the glomerular capillary wall, decreased urine content of IgM might be considered as a sign of recovery in the glomerular damage.
Asunto(s)
Albuminuria/orina , Glomerulonefritis/orina , Inmunoglobulina M/orina , Proteinuria/orina , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estadísticas no ParamétricasRESUMEN
Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.
Asunto(s)
Cistatinas/sangre , Tasa de Filtración Glomerular , Preeclampsia/sangre , Preeclampsia/diagnóstico , Adulto , Cistatina C , Femenino , Humanos , Hipertensión Renal/sangre , Hipertensión Renal/diagnóstico , Pruebas de Función Renal/métodos , EmbarazoRESUMEN
The objective of this study was to describe incidence and progression of diabetic retinopathy in relation to medical risk indicators as well as visual acuity outcome after a continuous follow-up period of 10 years in a Type 1 diabetic population treated under routine care. The incidence and progression of retinopathy and their association to HbA(1c), blood pressure, urinary albumin, serum creatinine levels, and insulin dosage were studied prospectively in 452 Type 1 diabetic patients. The degree of retinopathy was classified as no retinopathy, background, or sight-threatening retinopathy, i.e. clinically significant macular edema, severe nonproliferative, or proliferative retinopathy. Impaired visual acuity was defined as a visual acuity <0.5 and blindness as a visual acuity < or =0.1 in the best eye. In patients still alive at follow-up (n=344), 61% (69/114) developed any retinopathy, 45% (51/114) background retinopathy, and 16% (18/114) sight-threatening retinopathy. Progression from background to sight-threatening retinopathy occurred in 56% (73/131). In 2% (6/335), visual acuity dropped to <0.5 and in less than 1% (3/340) to < or =0.1. Patients who developed any retinopathy and patients who progressed to sight-threatening retinopathy had higher mean HbA(1c) levels over time compared to those who remained stable (P<.001 in both cases). Patients who developed any retinopathy had higher levels of mean diastolic blood pressure (P=.036), whereas no differences were seen in systolic blood pressure levels between the groups. Cox regression analysis, including all patients, showed mean HbA(1c) to be an independent risk indicator for both development and progression of retinopathy, whereas mean diastolic blood pressure was only a risk indicator for the incidence of retinopathy. Metabolic control is an important risk indicator for both development and progression of retinopathy, whereas diastolic blood pressure is important for the development of retinopathy in Type 1 diabetes. The number of patients who became blind during 10 years of follow-up was low.
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Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Retinopatía Diabética/epidemiología , Agudeza Visual , Adulto , Albuminuria , Antihipertensivos/uso terapéutico , Presión Sanguínea , Creatinina/sangre , Diabetes Mellitus Tipo 1/terapia , Nefropatías Diabéticas/complicaciones , Retinopatía Diabética/fisiopatología , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Insulina/administración & dosificación , Persona de Mediana Edad , Factores de RiesgoRESUMEN
The aim of the present study was to find clinical parameters affecting incidence and progression of nephropathy in type 2 diabetic patients. A prospective study for 10 years was performed in 385 type 2 diabetic patients (diabetes diagnosis > or =30 years) attending a hospital-based outpatient clinic. Medical risk indicators like diabetes duration, HbA(1c), and blood pressure were related to the development and progression of diabetic nephropathy. The 10-year incidence of microalbuminuria was 38% (n=95) and that of macroalbuminuria was 10% (n=26). Out of 103 patients with microalbuminuria, 38 developed macroalbuminuria. In 252 normoalbuminuric patients, the mean of the HbA(1c) (P<.05) levels obtained during the study were associated with a doubling of the fractional albumin clearance. In contrast, blood pressure levels, age, diabetes duration, type of diabetes treatment, BMI, and gender were not (Cox regression analysis). Among 133 patients with micro- or macroalbuminuria, 22 more than doubled their serum creatinine level, in contrast to only 6 of 252 patients without. With Cox regression analysis, systolic (P<.01), but not diastolic, blood pressure or HbA(1c) levels or the above mentioned risk factors were associated with a doubling in serum creatinine. A total of 19 patients developed uremia during the study, out of whom 6 were in need of dialysis and 1 has had a renal transplantation, and 14 (74%) died. HbA(1c) (P<.05) and systolic blood pressure (P<.001) levels were associated with development of uremia, but not diastolic blood pressure or the other parameters mentioned above. This study shows that poor metabolic control is associated with development and high blood pressure with progression of nephropathy in type 2 diabetic patients.
Asunto(s)
Presión Sanguínea , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/epidemiología , Adulto , Albuminuria , Antihipertensivos/uso terapéutico , Índice de Masa Corporal , Creatinina/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/mortalidad , Nefropatías Diabéticas/fisiopatología , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Regresión , Insuficiencia Renal/etiología , Insuficiencia Renal/terapia , Factores de Riesgo , Factores de TiempoRESUMEN
Both glomerular and tubular markers have been used to follow diabetic nephropathy. However, neither albumin nor proximal tubular markers have proven useful in prepubertal diabetes. Hence we studied two markers derived from the distal tubular cells, Tamm-Horsfall protein (THP) and epidermal growth factor (EGF). The urinary excretion of THP and EGF was examined in samples obtained during the first 20 days and 1 year after diagnosis of diabetes in children aged 4-15 years. Fourteen children without and 18 with ketonuria were examined, and 17 age-matched healthy children participated as controls. The excretion rate of EGF was increased at diagnosis, while that of THP was not. After 20 days of treatment the excretion of EGF had normalized, while the excretion of THP was decreased. Similar results were obtained after 1 year. In conclusion, in spite of good metabolic control a reduced excretion of THP persisted for at least 1 year after the diagnosis of diabetes. Whether the finding of reduced excretion of THP has any biological significance awaits further study.
Asunto(s)
Factor de Crecimiento Epidérmico/orina , Mucoproteínas/orina , Adolescente , Niño , Preescolar , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/orina , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Cetonas/orina , Masculino , Valores de Referencia , Factores de Tiempo , UromodulinaRESUMEN
BACKGROUND: The transport of large proteins across the glomerular capillary wall (GCW) may increase several fold in glomerular diseases. The occurrence of IgM in urine is a consequence of the presence of large defects or shunts in the GCW, whereas albuminuria is probably a result of an altered charge- and size-selectivity of the GCW. In order to examine whether patho-morphological differences influence the renal outcome in proteinuric glomerulopathies, we examined urinary excretion of IgM and albumin as prognostic markers of glomerular disease. METHODS: An observational study over a median of 41 (+/-3) months was conducted in 84 patients with biopsy-verified glomerular disease. The patients were subdivided into groups with low (< or =0.002) and high (>0.002) proteinuria selectivity index based upon IgM (IgM-SI), and into groups with low (< or =200 mg/mmol) and high (>200 mg/mmol) albumin creatinine index (ACI). RESULTS: In the high IgM-SI group, the median creatinine clearance (Ccr) decreased by 26%, and 62% of the patients decreased in Ccr by >5 ml/ min/year during the follow-up time. In comparison, the median Ccr decreased by 8% in the low IgM-SI group (P<0.001) and only 18% of the patients in this group deteriorated by >5 ml/min/year in the Ccr. Eleven (21%) of the 51 patients in the high IgM-SI group developed end-stage renal failure compared with none of the 33 patients in the low IgM-SI group. All the patients that progressed to uraemia had decreased Ccr (<60 ml/min) at entry into the study. However, among all these patients, only those with high IgM-SI, and none with low IgM-SI, developed end stage renal failure. The fall in Ccr did not differ significantly between the patients in high (12%) and low (16%) ACI groups. CONCLUSION: The results of this study indicate that an increased IgM-SI value is a stronger predictor of clinical outcome in proteinuric glomerulopathies than baseline albuminuria. This finding may reflect different patho-histological mechanisms influencing renal survival in glomerular diseases.
Asunto(s)
Glomerulonefritis/orina , Inmunoglobulina M/orina , Proteinuria , Adulto , Anciano , Anciano de 80 o más Años , Creatinina/sangre , Creatinina/orina , Progresión de la Enfermedad , Femenino , Glomerulonefritis/clasificación , Glomerulonefritis/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Resultado del Tratamiento , Uremia/fisiopatologíaRESUMEN
Renal biopsies were obtained from type 2 diabetic patients with elevated albumin excretion. The aim was to obtain quantitative structural data to correlate with clinical findings. Biopsies from 27 diabetic patients and 12 non-diabetic cases were analysed. Stereological methods were applied by light- and electron microscopy. Diabetic patients showed quantitatively markedly expressed diabetic glomerulopathy, but also an increase in glomerular volume, in prevalence of new-vessel formation at the vascular pole, prevalence of glomerular occlusion and in interstitial volume fraction. A significant correlation was not observed between the degree of interstitial and glomerular involvement. The glomerular hypertrophy is interpreted as a compensatory phenomenon, leading to preservation of filtration surface in the open glomeruli. Close correlation was seen between glomerulopathy and glomerular function, and also with the stage of retinopathy. New vessel formation at the vascular pole was most frequent in patients with proliferative retinopathy. Signs of non-diabetic glomerulopathy were not observed, but various atypical ultrastructural changes accompanying the advanced stages are illustrated. Our present findings correspond to data from type I diabetic patients. It is emphasised that all compartments of the kidney are affected by the diabetic state. It is suggested that the interstitial and glomerular lesions are influenced by different factors.
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Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/patología , Riñón/patología , Adulto , Anciano , Albuminuria/patología , Capilares/patología , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/fisiopatología , Retinopatía Diabética/patología , Humanos , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Microscopía Electrónica , Persona de Mediana EdadRESUMEN
The objective was to study the development and progression of heart disease in type 2 diabetic patients and to evaluate the influence of revascularisation procedures on its outcome. A 10-year observation study in 385 patients attending a hospital-based outpatient clinic was performed. A total of 156/385 patients developed myocardial infarction (n=68), angina (n=44), heart failure (n=34) or died (n=109). A high mortality was seen in patients with myocardial infarction (73%) and heart failure (71%), in contrast, to patients with angina (25%). Thirty patients had a coronary angiography because of angina, out of which 23 were revascularised. Four (17%) of patients with bypass surgery or angioplasty died compared with 57 (67%) of the patients with no intervention (p<0.001). The occurrence of myocardial infarction was associated with age (p<0.0001), and mean systolic (p<0.05) and diastolic (p<0.05) blood pressure and degree of albuminuria at entry (p<0.05). Heart failure was associated with age (p<0.0001), and mean HbA(1c) levels (p<0.05), while angina was associated with age only (p<0.05). Death was associated with age (p<0.0001), diabetes duration (p<0.05), mean diastolic blood pressure (p<0.05), and degree of albuminuria at entry (p<0.0001). This study shows a high incidence of heart disease in patients with type 2 diabetes. The prognosis was better in patients who had had a revascularisation procedure. Thus, a more active attitude towards revascularisation may potentially improve the prognosis for type 2 diabetic patients with atherosclerotic heart disease.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Cardiopatías/epidemiología , Adulto , Angina de Pecho/epidemiología , Angina de Pecho/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Progresión de la Enfermedad , Femenino , Cardiopatías/mortalidad , Cardiopatías/terapia , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/mortalidad , Revascularización Miocárdica/estadística & datos numéricos , Oportunidad Relativa , Pronóstico , Tasa de Supervivencia , Suecia/epidemiología , Resultado del TratamientoRESUMEN
The characteristics of the tubuloglomerular feedback (TGF) mechanism were examined in streptozotocin-diabetic rats. This model is known to induce damage in the distal tubular system and thus Tamm-Horsfall protein (THP) secretion. Three groups of male Sprague-Dawley rats were studied: (A) diabetic rats with blood glucose levels (BG)<19 mmol/l, (B) with BG>/=19 mmol/l, and (C) control rats. After 50 days, the diabetic rats had higher arterial blood pressure and increased TGF reactivity (delta P(SF)) than control rats. The proximal tubular free-flow pressure (P(T)) and stop-flow pressure (P(SF)) were reduced, while the glomerular filtration was normal. This indicates that the diabetic animals of this study were severely vasoconstricted. Inhibition of renal nitric oxide synthase (NOS) resulted in a greater increase of TGF reactivity in diabetic rats than in control rats. Diabetic rats also showed increased excretion rates of albumin and THP. The excretion rate of THP was associated with P(SF) (r=-0.88, p<0.01). In conclusion, diabetes mellitus was associated with an increased blood pressure and an increased TGF reactivity, which indicates that the diabetic rats were vasoconstricted. NOS inhibition increased the reactivity of TGF to greater extent in diabetic animals than in controls, indicating that the renal vasoconstriction was compensated for by an increased NO production.
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Diabetes Mellitus Experimental/fisiopatología , Glomérulos Renales/fisiopatología , Túbulos Renales/fisiopatología , Óxido Nítrico/biosíntesis , Animales , Presión Sanguínea , Inhibidores Enzimáticos/farmacología , Retroalimentación , Tasa de Filtración Glomerular , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , VasoconstricciónRESUMEN
The proteinuria selectivity index (SI) describes changes of the glomerular permeability for macromolecules. In the present study, we examine the implications of SI as a diagnostic (199 patients) and a prognostic (49 patients) marker in glomerular diseases. Using SI based on alpha(2)-macroglobulin (alpha(2)-M-SI) or on IgM (IgM-SI) we found that minimal change nephropathy could be discriminated by low SI values and crescentic necrotizing glomerulonephritis by high SI values compared to other diseases. SI based on IgG (IgG-SI) was less useful in determining specific diagnoses. During a follow-up of 46 months creatinine clearance (Cr cl) decreased 36% in a group of patients with high IgG-SI (>0.2) and 38% in a group of patients with high IgM-SI (>1.5(-3)) compared to only 8% in patients with low IgG-SI (
Asunto(s)
Enfermedades Renales/diagnóstico , Glomérulos Renales/fisiopatología , Proteinuria/diagnóstico , Adolescente , Adulto , Anciano , Femenino , Humanos , Inmunoglobulina G/orina , Inmunoglobulina M/orina , Enfermedades Renales/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Proteinuria/fisiopatología , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
In summary, diabetic nephropathy is characterized by a multifactorial disease process. The present survey points to several factors that are treatable by available drugs. We must now consider prophylactic treatment of patients with poor metabolic control not only to lower blood glucose levels, but also to protect against the harmful effects of glucose. ACE inhibitors and several other available drugs have such effects.
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Nefropatías Diabéticas/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Glucemia/análisis , Captopril/uso terapéutico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Progresión de la Enfermedad , Humanos , Hipertensión/complicaciones , Riñón/fisiopatología , PronósticoRESUMEN
OBJECTIVE: In diabetic nephropathy there is a decrease in glycosaminoglycans (GAG) in basement membranes and in Tamm-Horsfall protein (THP) in the distal tubules of the kidneys. Since GAG is present in both glomerular and tubular basement membranes, and the synthesis of both GAG and THP involves glycosylation, this study was carried out in order to investigate whether urinary excretion of these substances is interrelated. MATERIAL AND METHODS: 24-h urinary collections were analysed. A total of 94 diabetic patients were grouped in accordance with the urinary albumin excretion rate as normo- (<20 microg/min) (n = 35), micro- (20-200 microg/min) (n = 30) and macroalbuminuria (>200 microg/min) (n = 29). RESULTS: In comparison with 26 control subjects, the excretion rate of GAG was decreased in patients with micro- and macroalbuminuria and excretion of Tamm-Horsfall protein in patients with macroalbuminuria. The excretion rates of GAG and THP were associated (r = 0.64, p < 0.001) and correlated with creatinine clearance (r= 0.46 and r= 0.53, p < 0.001; respectively) but not with levels of HbA1c. CONCLUSIONS: In conclusion, albuminuria was associated with decreased urinary excretion of sulphated GAGs, which was associated with the excretion rate of Tamm-Horsfall protein, indicating that excretion of GAG was associated with distal tubular dysfunction in diabetic patients.
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Diabetes Mellitus Tipo 1/orina , Nefropatías Diabéticas/fisiopatología , Glicosaminoglicanos/orina , Mucoproteínas/orina , Albuminuria/etiología , Análisis de Varianza , Diabetes Mellitus Tipo 1/complicaciones , Glicosaminoglicanos/biosíntesis , Humanos , Riñón/fisiopatología , UromodulinaRESUMEN
BACKGROUND: In diabetic nephropathy, a reduction in negative membrane charge in the glomerular filter, i.e., the number of sulphated groups of glycosaminoglycans, has been argued to lead to increases in excretion of negatively charged molecules, such as albumin and IgG4. However, albuminuria and an increased excretion rate of IgG may also be caused by an increase in radius or number of glomerular large pores. METHODS: Timed urinary excretion rates of sulphated glycosaminoglycans, albumin, and IgG2, IgG4, and IgM were analyzed in 94 patients with insulin-dependent diabetes mellitus with different degrees of nephropathy and compared with the excretion rates in 26 control subjects. Sulphated glycosaminoglycans were measured spectrophotometrically after addition of 1, 9-dimethylmethylene blue. Albumin and immunoglobulins were measured by immunoassays. RESULTS: With increases in the albumin excretion rate the excretion of IgG2, IgG4, and IgM also increased, in contrast to a decrease in glycosaminoglycans and the ratio between IgG2 and IgG4 (selectivity index). This index decreased from 6.2 to 0.7 (median; p < 0.01). However, with linear regression analysis the excretion rates of albumin and immunoglobulins were not associated with those of glycosaminoglycans. CONCLUSION: In diabetic nephropathy changes in both large-pore number and in charge selectivity may be pathogenic mechanisms for albuminuria.
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Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/orina , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/orina , Glicosaminoglicanos/orina , Inmunoglobulinas/orina , Glomérulos Renales/metabolismo , Adulto , Albuminuria/metabolismo , Albuminuria/orina , Estudios de Casos y Controles , Electroquímica , Femenino , Glicosaminoglicanos/química , Humanos , Inmunoglobulinas/química , Masculino , Persona de Mediana Edad , Peso MolecularRESUMEN
OBJECTIVE: The study was performed in order to evaluate to what extent hypertension or diabetes mellitus may affect the urinary excretion rate of Tamm-Horsfall protein. MATERIALS AND METHOD: The urinary excretion rates of albumin and Tamm-Horsfall protein, a measure of glomerular and distal tubular function, respectively were measured in patients with essential hypertension (n = 17) and in type 1 diabetes with (n = 20) or without nephropathy (n = 8) and in apparently healthy subjects (n = 10). RESULTS: Mean 24-h ambulatory blood pressure measurements showed higher blood pressure levels in the hypertensive (167/ 106 mmHg, p < 0.001) than in the diabetic patients with (136/84 mmHg) and without nephropathy (121/74 mmHg) and in healthy subjects (122/76 mmHg). Day and night ratios of systolic and diastolic blood pressure levels were not different among the four groups. Urinary albumin excretion rate was increased in patients with hypertension (30.8 x/ 3.4 microg/min; geometric mean x/tolerance factor; p < 0.001) and diabetes with nephropathy (462 x/ 3.5 microg/min; p < 0.001) compared with diabetic patients without nephropathy and healthy subjects (4.6 x/ 1.9 and 3.7 x/ 1.5 microg/min, respectively). The Tamm-Horsfall protein excretion rate was decreased in patients with diabetic nephropathy (11.6 x/ 3.5 microg/min) compared to patients with hypertension (36.3 x/2.1 1g/min; p < 0.01), diabetes without nephropathy (39.2 x/ 2.0 microg/min; p < 0.05) and healthy subjects (63.0 x/ 1.4 microg/min; p < 0.001), whereas no differences were found among the latter three groups. CONCLUSION: These data indicate that high blood pressure may be associated with albuminuria, while a decrease in excretion rate of Tamm-Horsfall protein may be associated with diabetic nephropathy. These associations need to be studied in a larger population.
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Diabetes Mellitus Tipo 1/orina , Hipertensión/orina , Mucoproteínas/orina , Anciano , Albuminuria/fisiopatología , Albuminuria/orina , Análisis de Varianza , Presión Sanguínea , Enfermedad Crónica , Creatinina/análisis , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Nefropatías Diabéticas/fisiopatología , Nefropatías Diabéticas/orina , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , UromodulinaRESUMEN
BACKGROUND: Alterations of the charge-selective properties of the glomerular capillary wall are important constituents of the pathogenesis of many glomerular diseases. Thus, differences in the degree of such changes could be of help in understanding the mechanisms governing the transport of macromolecules across the glomerular capillary wall. METHODS: The ratio between urine concentrations of neutral IgG2 and negatively charged IgG4 (IgG2/IgG4-ratio) was measured in 150 proteinuric patients and 21 healthy controls. The patients were subdivided into seven biopsy verified diagnostic groups. RESULTS: The study revealed decreased IgG2/ IgG4-ratio in membranous glomerulonephritis (0.57) compared to healthy controls (2.09) and to all other diagnosis groups; crescentic necrotizing glomerulonephritis (1.28), diffuse proliferative glomerulonephritis (1.10), IgA nephropathy (1.11), mesangial proliferative glomerulonephritis (1.55), minimal change nephropathy (1.00), and nephrosclerosis secondary to hypertension (1.06). Although not statistically significant, there was a tendency towards lower IgG2/IgG4-ratio values in all the studied glomerular diseases compared to healthy controls. CONCLUSIONS: Since IgG is transported entirely through the large pores of the glomerular basement membrane decreased IgG2/IgG4-ratio implies that this pathway is strongly influenced by the charge-selective properties of the glomerular capillary wall. The conclusion that could be drawn from that is that the large pore radius must be discrete, in the order of 80-90 A, and thus not non-discriminatory to macromolecules as previously thought.
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Glomerulonefritis/metabolismo , Inmunoglobulina G/clasificación , Inmunoglobulina G/orina , Glomérulos Renales/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Transporte Biológico , Niño , Femenino , Humanos , Sustancias Macromoleculares , Masculino , Persona de Mediana EdadRESUMEN
Abnormal renal vasomotor tone exists in the early stages of diabetes mellitus. Insulin has been proposed to modulate renal function and to possess vasodilatory effects. The present study was initiated in order to evaluate the direct effect of insulin on isolated renal arteries. Twelve insulin-treated streptozotocine diabetic rats with diabetes for 50 days were compared with 15 weight-matched control rats. The contractile responses to 60 mM K+ and 10(-4) M noradrenaline, and the insulin- (0.8-6.4 I.U./ml) induced relaxation of vessels precontracted with noradrenaline, were similar in diabetic and control rats. There was a tendency towards greater relaxation in diabetic (71%) than in control rats (54%). Nw-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) given before noradrenaline tended to attenuate the insulin-induced relaxation, while addition of L-arginine (10(-6) M) to L-NAME attenuated the relaxation in diabetic but increased it in control rats (P < 0.05). The effect of insulin was tested further in control rats and was not influenced by administration of a single dose (10(-6) M) of indomethacin or propranolol given instead of L-NAME. The effect of a single dose of methylene-blue, given before noradrenaline, was tested in control rats in varying doses between 2 x 10(-6) and 2 x 10(-4) M. In the highest concentration it made no difference whether insulin was given or not and there was a similar relaxing effect in diabetic and control arteries. In conclusion, the present study showed that insulin per se has a relaxing effect on renal arteries. There was a tendency to greater relaxation in diabetic than in control rats, an effect which was attenuated by in-vitro-pretreatment with L-NAME as well as with L-NAME and L-arginine in diabetic vessels, while relaxation was increased in control vessels. This may indicate that the effect of insulin may be mediated through nitric oxide in diabetic but not in control rats. The effects of insulin in control vessels were not modified in vitro by indomethacin, propranolol or methylene-blue.
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Diabetes Mellitus Experimental/fisiopatología , Insulina/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Arteria Renal/efectos de los fármacos , Animales , Diabetes Mellitus Experimental/inducido químicamente , Técnicas In Vitro , Masculino , Relajación Muscular/fisiología , Músculo Liso Vascular/fisiopatología , Ratas , Ratas Sprague-Dawley , Arteria Renal/fisiologíaRESUMEN
BACKGROUND: The proteinuria selectivity index (SI) may be used to describe changes of the glomerular permeability for macromolecules in glomerular diseases. Proteins the size of alpha 2-macroglobulin (alpha 2 M) or IgM cannot normally pass the glomerular barrier, whereas IgG can pass through the large pores of glomerular basement membrane. Comparison of the clearance of the three high-molecular-weight proteins to that of albumin may be useful in characterization and diagnosis of different glomerular diseases as well as in understanding of the permeability characteristics of the glomerular filter. METHODS: Three types of SI, each calculated as a ratio of clearance of either IgG, alpha 2M or IgM to that of albumin, were measured in 199 proteinuric patients. The patients were subdivided into eight different biopsy-verified glomerular diseases. RESULTS: Two diagnoses could be clearly distinguished using SI based on alpha 2M (alpha 2 M SI) or IgM (IgM SI). Both alpha 2M SI and IgM SI were significantly lower in minimal change nephropathy and higher in crescentic necrotizing glomerulonephritis than in all the other diagnoses. The SI based on IgG (IgG SI) was less useful in determining specific diagnoses, since patients with minimal change nephropathy could not be distinguished from those with other types of primary glomerulonephritis and patients with crescentic necrotizing glomerulonephritis did not differ from those with diabetic nephropathy. CONCLUSIONS: The findings of this study indicate that alpha 2M SI and IgM SI are superior to IgG SI in characterization of glomerular disorders and might replace the IgG SI for this purpose.