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【文摘发布】一项随机对照临床实验：他克莫司
Tacrolimus monotherapy in membranous nephropathy: A randomized controlled trial
M Praga1, V Barrio2, G Fernández Juárez2 and J Luño3 For the GRUPO ESPAÑOL DE ESTUDIO DE LA NEFROPATÍA MEMBRANOSA
1Hospital 12 de Octubre, Madrid, Spain
2Fundación Hospital Alcorcón, Alcorcón, Madrid, Spain
3Hospital Gregorio Marañón, Madrid, Spain
Correspondence: M Praga, Servicio de Nefrología, Hospital 12 de Octubre, Avda de Córdoba s/n, Madrid 28041, Spain. E-mail: mpragat@senefro.org
Abstract
Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.
为了大家更好地了解这项临床实验，特将其方法也一并公布出来，供大家参考，当然如能翻译成中文那是最好不过了。
MATERIALS AND METHODS
This study was a prospective, randomized, parallel, open-label, and controlled trial conducted in 13 centers in Spain between January 2003 and September 2006. The study protocol was reviewed and approved by each center's Ethic Committee and written informed consent was provided by all participants. The entry criteria were a biopsy-proven MGN, age between 18 and 70 years, nephrotic-range proteinuria (>3.5 g/24 h) accompanied by hypoalbuminemia (serum albumin <3 g/dl) during at least a 9-month period before screening and an eGFR by Cockroft–Gault formula 50 ml/min/1.73 m2. Included patients who also had to be treated with an ACEI or an ARB at their maximal tolerated doses for at least 2 months before screening. Exclusion criteria included the diagnosis of diabetes mellitus, malignancy, systemic lupus erythematosus, or any other systemic disease known to be associated with secondary MGN, infections (including positive test for hepatitis C and B virus and HIV) and patients treated with steroids or immunosuppressive therapy within the 6-month period before screening.
Patients were randomized either to a control group or to a group treated with tacrolimus (treatment group). Randomization was performed by the clinical coordinating center using a table of random numbers and was stratified by centers. Allocation concealment was performed by enclosing assignments in sequentially numbered, opaque-closed envelopes. All the patients were instructed to maintain the same doses of ACEI or ARB that they were taking at randomization until the end of the study. Target BP was <130/80 mm Hg in both groups; other antihypertensive drugs were prescribed in addition of ACEI/ARB in those patients who did not reach these target values. Target low-density lipoprotein cholesterol was <160 mg/dl. Statin doses were increased, or treatment with these drugs was initiated in patients who did not reach this low-density lipoprotein cholesterol level in spite of dietary advice.
Patients randomized to the treatment group started tacrolimus at a dose of 0.05 mg/kg/day, divided into two daily doses at 12-h interval. Later doses were adjusted to achieve a whole blood 12-h trough level between 3 and 5 ng/ml. When a remission was not obtained after the first 2 months of treatment, doses were increased to achieve levels between 5 and 8 ng/ml. Tacrolimus treatment was continued for 12 months and then gradually tapered off for the next 6 months; a 25% tacrolimus dose reduction was indicated at months 12, 14, and 16 and treatment was withdrawn by month 18.
Follow-up visits were scheduled monthly during the first 4 months and thereafter every 2 months until month 18. In addition, patients randomized to the treatment group were controlled weekly during the first month, to adjust tacrolimus doses by whole blood levels, to avoid acute renal function worsening and to watch over any possible tacrolimus intolerance. At each visit, a complete physical examination was performed, including BP. BP was measured after 5 min of rest at a sitting position; the average of two BP measurements was recorded. At each visit, blood was sampled for standard hemogram, SCr, sodium, potassium, glucose, total proteins, albumin, total cholesterol, and high-density lipoprotein and low-density lipoprotein fractions, triglycerides, and trough levels of tacrolimus. A 24-h urine collection was obtained at every visit, and 24-h excretion of creatinine, protein, sodium, potassium, and urea were measured; eGFR was calculated at every visit.
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作者:admin@医学,生命科学 2011-03-14 05:12
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