RESUMEN
Inconsistent identification of reasons for removal from the liver transplant waiting list by Organ Procurement and Transplantation Network (OPTN) regions may contribute to regional variability in wait-list death rates. We analyzed OPTN and Social Security Administration (SSA) reported deaths of 103 364 liver transplant candidates listed May 8, 2003-April 17, 2011, and determined regional variability in risk of death attributable to differences in use of OPTN removal codes. Only 26% of candidates removed as "too sick" died within 90 days of delisting; 6335 deaths after delisting were not reported to OPTN. The ratio of number of candidates removed as "too sick" to number who died on the waiting list varied by region from 0.23 to 0.94, indicating substantial variability in use of removal codes. Including SSA-reported deaths within 90 days of delisting reduced regional variability in risk of death by 48% compared with deaths on the list alone, and by 35% compared with deaths plus the "too sick" designation. Codes for delisting liver transplant candidates are inconsistently applied among OPTN regions, spuriously elevating estimated regional variability in risk of wait-list death. This variability is ameliorated by including SSA- reported deaths within 90 days of delisting.
Asunto(s)
Fallo Hepático/mortalidad , Trasplante de Hígado/normas , Obtención de Tejidos y Órganos/métodos , Listas de Espera , Comorbilidad , Humanos , Fallo Hepático/terapia , Modelos de Riesgos Proporcionales , Sistema de Registros , Riesgo , Factores de Tiempo , Estados Unidos , United States Social Security AdministrationRESUMEN
In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.
Asunto(s)
Enfermedades Cardiovasculares/complicaciones , Pruebas de Función Renal , Trasplante de Riñón , Adulto , Anciano , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Creatinina/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.
Asunto(s)
Hemodiálisis en el Domicilio , Fallo Renal Crónico/terapia , Adulto , Anciano , Diseño de Equipo , Femenino , Hemodiálisis en el Domicilio/efectos adversos , Hemodiálisis en el Domicilio/instrumentación , Hemodiálisis en el Domicilio/mortalidad , Humanos , Hiperfosfatemia/etiología , Hiperfosfatemia/terapia , Hipertensión/etiología , Hipertensión/terapia , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/terapia , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , América del Norte , Cooperación del Paciente , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new-onset late graft dysfunction (N = 337). We found inflammation ('iatr') and tubulitis ('tatr') in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death-censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10-4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16-5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.
Asunto(s)
Trasplante de Riñón/patología , Túbulos Renales/patología , Nefritis/patología , Atrofia , Biopsia , Estudios de Cohortes , Creatinina/sangre , Estudios Transversales , Femenino , Fibrosis , Rechazo de Injerto/mortalidad , Humanos , Técnicas In Vitro , Masculino , Nefritis/sangre , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Medición de Riesgo , Índice de Severidad de la Enfermedad , Trasplante HomólogoRESUMEN
We are studying two cohorts of kidney transplant recipients, with the goal of defining specific clinicopathologic entities that cause late graft dysfunction: (1) prevalent patients with new onset late graft dysfunction (cross-sectional cohort); and (2) newly transplanted patients (prospective cohort). For the cross-sectional cohort (n = 440), mean time from transplant to biopsy was 7.5 +/- 6.1 years. Local pathology diagnoses included CAN (48%), CNI toxicity (30%), and perhaps surprisingly, acute rejection (cellular- or Ab-mediated) (23%). Actuarial rate of death-censored graft loss at 1 year postbiopsy was 17.7%; at 2 years, 29.8%. There was no difference in postbiopsy graft survival for recipients with versus without CAN (p = 0.9). Prospective cohort patients (n = 2427) developing graft dysfunction >3 months posttransplant undergo 'index' biopsy. The rate of index biopsy was 8.8% between 3 and 12 months, and 18.2% by 2 years. Mean time from transplant to index biopsy was 1.0 +/- 0.6 years. Local pathology diagnoses included CAN (27%), and acute rejection (39%). Intervention to halt late graft deterioration cannot be developed in the absence of meaningful diagnostic entities. We found CAN in late posttransplant biopsies to be of no prognostic value. The DeKAF study will provide broadly applicable diagnostic information to serve as the basis for future trials.
Asunto(s)
Supervivencia de Injerto/inmunología , Biopsia , Humanos , PronósticoRESUMEN
The nonspecific diagnoses 'chronic rejection''CAN', or 'IF/TA' suggest neither identifiable pathophysiologic mechanisms nor possible treatments. As a first step to developing a more useful taxonomy for causes of new-onset late kidney allograft dysfunction, we used cluster analysis of individual Banff score components to define subgroups. In this multicenter study, eligibility included being transplanted prior to October 1, 2005, having a 'baseline' serum creatinine < or =2.0 mg/dL before January 1, 2006, and subsequently developing deterioration of graft function leading to a biopsy. Mean time from transplant to biopsy was 7.5 +/- 6.1 years. Of the 265 biopsies (all with blinded central pathology interpretation), 240 grouped into six large (n > 13) clusters. There were no major differences between clusters in recipient demographics. The actuarial postbiopsy graft survival varied by cluster (p = 0.002). CAN and CNI toxicity were common diagnoses in each cluster (and did not differentiate clusters). Similarly, C4d and presence of donor specific antibody were frequently observed across clusters. We conclude that for recipients with new-onset late graft dysfunction, cluster analysis of Banff scores distinguishes meaningful subgroups with differing outcomes.
Asunto(s)
Análisis por Conglomerados , Creatinina , Biopsia , Complemento C4b , Creatinina/sangre , Supervivencia de Injerto , Humanos , Fragmentos de Péptidos , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/patología , Donantes de Tejidos , Resultado del TratamientoRESUMEN
Death with function causes half of late kidney transplant failures, and cardiovascular disease (CVD) is the most common cause of death in these patients. We examined the use of potentially cardioprotective medications in a prospective observational study at seven transplant centers in the United States and Canada. Among 935 patients, 87% received antihypertensive medications at both 1 and 6 months after transplantation. Similar antihypertensive regimens were used for patients with and without diabetes and CVD, but with wide variability among centers. In contrast, while 44% of patients were on angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) at the time of transplantation, the proportion taking these agents dropped to 12% at month 1, then increased to 24% at 6 months. Fewer than 30% with CVD or diabetes received ACEI/ARB therapy 6 months posttransplant. Aspirin use was uncommon (<40% of patients). Even among those with diabetes and/or CVD, fewer than 60% received aspirin and only half received a statin at 1 and 6 months. This study demonstrates marked variability in the use of cardioprotective medications in kidney transplant recipients, a finding that may reflect, among several possible explanations, clinical uncertainty due the lack of randomized trials for these medications in this population.
Asunto(s)
Cardiotónicos/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Trasplante de Riñón/efectos adversos , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Aspirina/uso terapéutico , Canadá , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estados UnidosRESUMEN
United Network for Organ Transplantation (UNOS) policy 3.6.4.5.1 provides exception points to patients diagnosed with hepatopulmonary syndrome (HPS) to compensate for their reported increased mortality risk. We compared pre- and posttransplant and overall outcomes in 255 patients receiving exception points under this policy (HPS policy patients) with 32 358 nonexception control patients listed in the model for end-stage liver disease (MELD) era to determine whether the intent of the policy is being met. Overall, 92.5% of HPS policy patients versus 45.5% of controls had been transplanted, 5.1% versus 31.2% remained on waiting list and 1.5% versus 14.1% had died while awaiting transplant (p < 0.0001 for each comparison). Relative risk (RR) of death for HPS policy patients compared to controls was 0.158 (confidence interval [CI]: 0.059-0.420, p = 0.0002) pretransplant, and 0.827 (CI: 0.587-1.170, p = 0.28) posttransplant. Overall (combined waitlist and posttransplant) RR of death was 0.514 (CI: 0.374-0.707, p = 0.00004) compared with controls. After adjustment for laboratory MELD, overall RR was 0.807 (CI: 0.587-1.110, p = 0.19), indicating that HPS policy patients' mortality risk would be similar to that of controls had they been listed with their laboratory MELD score. HPS policy patients have a significant pretransplant survival advantage over standard liver transplant candidates because of the exception points awarded, and have similar posttransplant survival. Better criteria for diagnosing and grading of HPS are required.
Asunto(s)
Asignación de Recursos para la Atención de Salud/normas , Política de Salud , Síndrome Hepatopulmonar/cirugía , Trasplante de Hígado/estadística & datos numéricos , Asignación de Recursos/métodos , Obtención de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/normas , Humanos , Selección de Paciente , Asignación de Recursos/estadística & datos numéricos , Obtención de Tejidos y Órganos/estadística & datos numéricos , Estados Unidos , Listas de EsperaRESUMEN
The Modification of Diet in Renal Disease (MDRD) Study examined the effects of strict blood pressure control and dietary protein restriction on the progression of kidney disease. Here, we retrospectively evaluated outcomes of nondiabetic participants with stages 2-4 chronic kidney disease (CKD) from randomized and nonrandomized cohorts of the MDRD Study. Kidney failure and survival status through December of 2000, were obtained from the US Renal Data System and the National Death Index. Event rates were calculated for kidney failure, death, and a composite outcome of death and kidney failure. In the 1666 patients, rates for kidney failure were four times higher than that for death. Kidney failure was a more likely event than death in subgroups based on baseline glomerular filtration rate, proteinuria, kidney disease etiology, gender, and race. It was only among those older than 65 that the rate for death approximated that for kidney failure. In contrast to other populations with CKD, our study of relatively young subjects with nondiabetic disease has found that the majority of the participants advanced to kidney failure with a low competing risk of death. In such patients, the primary emphasis should be on delaying progression of kidney disease.
Asunto(s)
Dieta con Restricción de Proteínas , Enfermedades Renales/dietoterapia , Enfermedades Renales/fisiopatología , Insuficiencia Renal/mortalidad , Adolescente , Adulto , Anciano , Determinación de la Presión Sanguínea , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Enfermedades Renales/complicaciones , Masculino , Persona de Mediana Edad , Insuficiencia Renal/etiología , Estudios Retrospectivos , Factores Sexuales , Resultado del TratamientoRESUMEN
The shortage of deceased donor kidneys and livers for transplantation has prompted the use of organs from donors deceased after cardiac death (DCD). We used the UNOS database to examine patient and graft survival following transplantation of DCD organs compared to those following grafts from donors deceased after brain death (DBD; for livers, grafts from donors < 60 years old were labeled '< 60 yrs'). Of 44035 deceased donor kidney transplant recipients, 1177 (3%) received a DCD kidney. There was no difference in patient or graft survival at 5 years (DCD vs. DBD: 81.3% vs. 80.8% and 66.9% vs. 66.5%; p = 0.70 and p = 0.52 respectively). Of 24688-deceased donor liver transplant recipients, 345 (1.4%) were from DCD donors and 20289 (82%) were from '< 60 yrs' DBD donors. Three-year patient and graft survival were inferior in the DCD group (DCD vs. '< 60 yrs' DBD: 77% vs. 80% and 65% vs. 75%; p = 0.016 and p < 0.0001 respectively) but were comparable to current alternatives, '>/= 60 yrs' DBD livers (donor age >/= 60) and split livers. DCD livers are a reasonable option when death is imminent. Our study demonstrates good outcomes using DCD kidneys and livers and encourages their use.
Asunto(s)
Muerte , Trasplante de Riñón/mortalidad , Trasplante de Hígado/mortalidad , Donantes de Tejidos , Adulto , Muerte Encefálica , Femenino , Supervivencia de Injerto , Humanos , Trasplante de Riñón/normas , Trasplante de Hígado/normas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
We described the characteristics in a referred cohort of type II diabetic patients in the Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes study evaluating the global prevalence and determinants of microalbuminuria (MA). A cross-sectional study evaluating 32,208 type II diabetic patients without known albuminuria from 33 countries was performed. Overall, 8057 patients were excluded, either because of prior known proteinuria or non-diabetic nephropathy (3670), or because of invalid urine collections (4387). One single random urinary albumin/creatinine ratio was obtained in 24,151 patients (75%). The overall global prevalence of normo-, micro-, and macroalbuminuria was 51, 39, and 10%, respectively. The Asian and Hispanic patients had the highest prevalence of a raised urinary albumin/creatinine ratio (55%) and Caucasians the lowest (40.6), P<0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P<0.0001. Estimated glomerular filtration rate was below 60 ml/min/1.73 m(2) in 22% of the 11,573 patients with available data. Systolic BP below 130 mmHg was found in 33 and 43% had an HbA1c below 7%. The frequency of patients receiving aspirin was 32%, statins 29%, and BP-lowering therapy 63%. A high prevalence globally of MA and reduced kidney function, both conditions associated with enhanced renal and cardiovascular risk, was detected in type II diabetic patients without prior known nephropathy. Early detection, monitoring of vascular complications, and more aggressive multifactorial treatment aiming at renal and vascular protection are urgently needed.
Asunto(s)
Albuminuria/epidemiología , Albuminuria/etiología , Diabetes Mellitus Tipo 2/complicaciones , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Derivación y Consulta , Factores de RiesgoRESUMEN
BACKGROUND: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. METHODS: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. RESULTS: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. CONCLUSIONS: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Tetrazoles/uso terapéutico , Adulto , Anciano , Amlodipino/efectos adversos , Amlodipino/uso terapéutico , Antihipertensivos/efectos adversos , Compuestos de Bifenilo/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Creatinina/sangre , Nefropatías Diabéticas/complicaciones , Método Doble Ciego , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Irbesartán , Fallo Renal Crónico/prevención & control , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Tetrazoles/efectos adversosRESUMEN
A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Hipertensión/tratamiento farmacológico , Tetrazoles/uso terapéutico , Adulto , Anciano , Amlodipino/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Angiopatías Diabéticas/complicaciones , Nefropatías Diabéticas/etiología , Método Doble Ciego , Femenino , Humanos , Hipertensión/complicaciones , Irbesartán , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteinuria/diagnóstico , Proteinuria/etiologíaRESUMEN
BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. METHODS: We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. CONCLUSION: This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.
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Ciclosporina/uso terapéutico , Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Esteroides/uso terapéutico , Adulto , Ciclosporina/efectos adversos , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Glomerulonefritis Membranosa/orina , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Estudios Prospectivos , Proteinuria/etiología , Recurrencia , Retratamiento , Método Simple Ciego , Resultado del TratamientoRESUMEN
The hammerhead ribozyme is a catalytic RNA that requires divalent metal cations for activity under moderate ionic strength. Two important sites that are proposed to bind metal ions in the hammerhead ribozyme are the A9/G10.1 site, located at the junction between stem II and the conserved core, and the scissile phosphate (P1.1). (31)P NMR spectroscopy in conjunction with phosphorothioate substitutions is used in this study to investigate these putative metal sites. The (31)P NMR feature of a phosphorothioate appears in a unique spectral window and can be monitored for changes upon addition of metals. Addition of 1-2 equiv of Cd(2+) to the hammerhead with an A9-S(Rp) or A9-S(S)(Rp) substitution results in a 2-3 ppm upfield shift of the (31)P NMR resonance. In contrast, the P1.1-S(Rp) and P1.1-S(Sp) (31)P NMR features shift slightly and in opposite directions, with a total change in delta of =0.6 ppm with addition of up to 10 equiv of Cd(2+). No significant shifts are observed for an RNA.RNA duplex with a single, internal phosphorothioate modification upon addition of Cd(2+). Data obtained using model compounds including diethyl phosphate/thiophosphate, AMP, and AMPS, show that a Cd(2+)-S interaction yields an upfield shift for the (31)P NMR resonance, even in the case of a weak coordination such as with diethyl thiophosphate. Taken together, these data predict that Cd(2+) has a high affinity for the A9 site and suggest that there is flexibility in metal coordination within the binding pocket. Cd(2+) interactions with the cleavage site P1.1-S positions are weaker and appear to be stereospecific. These data have implications for mechanisms that have been proposed to explain the influence of metal ions on hammerhead ribozyme activity. These experiments also show the potential utility of (31)P NMR spectroscopy in conjunction with phosphorothioates as a probe for metal binding sites in nucleic acids.
Asunto(s)
Metales/química , Fosfatos/química , ARN Catalítico/química , Tionucleótidos/química , Sitios de Unión , Cadmio/química , Hidrólisis , Magnesio/química , Resonancia Magnética Nuclear Biomolecular , Organofosfatos/química , Isótopos de FósforoRESUMEN
The roles of metals in the phosphodiester bond cleavage reaction performed by the hammerhead ribozyme are under investigation. In this study, the apparent affinities and the abilities of several different metals to support ribozyme activity are reported. The relative affinities of divalent cations for the hammerhead ribozyme are determined by measuring their ability to release bound Mn2+. The EPR-detected Mn2+ competition studies give an order of apparent affinity of Mn2+ approximately Co2+ approximately Zn2+ > Cd2+ >> Mg2. This ordering generally follows the trend of maximum rates of cleavage determined at pH 7.0, 0.1 M NaCl, and saturating metal concentrations, of Mn2+ > Co2+ > Cd2+ > Mg2+. The maximum rate is observed for Mn2+ under these conditions and may be related to the high affinity, low pKa and low deltaHhyd of this ion. Substitution of phosphorothioates 5' to each of the nine adenosines in the enzyme strand yields a change in the Mn2+ binding properties of the hammerhead complex. In the phosphorothioate-substituted hammerhead complex, eight to nine Mn2+ bind in two types of classes: 'type 1' (n = 1+/-0.3, Kd = 1.1+/-1 microM) and weaker 'type 2' (n = 7.7+/-0.3, Kd = 125+/-27 microM). The multiple phosphorothioate substitutions result in the loss of two to three of the higher affinity sites observed in the unmodified ribozyme. Metal competition studies with the phosphorothioate-substituted ribozyme indicate that the relative affinities of the metals are Cd2+ > Zn2+ > Co2+, Mg2+ with the number of Mn2+ displaced and apparent affinity of the thiophilic Cd2+ most affected by the phosphorothioate substitutions.
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Cationes Bivalentes/metabolismo , Manganeso/metabolismo , Conformación de Ácido Nucleico , ARN Catalítico/metabolismo , Tionucleótidos/química , Cadmio/química , Cationes Bivalentes/química , Cobalto/química , ADN/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Cinética , Magnesio , Manganeso/química , Estructura Molecular , ARN Catalítico/química , Zinc/químicaRESUMEN
STUDY OBJECTIVE: To compare serum and intracellular pharmacokinetics of azithromycin in healthy volunteers and patients with diabetes. DESIGN: Open-label, parallel study. SETTING: Clinical research center. SUBJECTS: Twelve patients with diabetes and 12 healthy volunteers. INTERVENTIONS: Subjects were given a single 500-mg dose of azithromycin followed by 250 mg/day for 2 days. Blood samples were obtained just before and after the third dose for up to 24 hours for serum and 168 hours for intracellular measurement of azithromycin. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were calculated by noncompartmental methods and compared with a t test. The groups did not differ in maximum concentration, time to maximum concentration, or area under the concentration-time curve in serum or polymorphonuclear cells (PMNs). Differences in the PMN:serum ratio were observed at the 24-hour time point (healthy 1209 +/- 432, diabetic 859 +/- 286, p=0.051). CONCLUSION: In general, the pharmacokinetics of azithromycin are comparable in diabetics and healthy volunteers. Accumulation of drug in macrophages was slightly lower in patients.
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Antibacterianos/farmacocinética , Azitromicina/farmacocinética , Diabetes Mellitus/metabolismo , Neutrófilos/metabolismo , Adulto , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.