| BackgroundThe renin-angiotensin-aldosterone system (RAAS) has an important role in the progression of chronic kidney diseases (CKD).Interruption of the RAAS with renin angiotensin system inhibitor such as angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB), alone or in combination, has become a leading therapeutic strategy to slow the progression of CKD.However, lots of clinical trials of ACEI and ARB, plasma aldosterone levels, after an initial decline, have been shown to increase in some patients over the long-term (the aldosterone breakthrough phenomenon). Aldosterone, a final effector of the RAAS, has a significant role in the pathogenesis of CKD. The unopposed aldosterone exacerbated glomerulosclerosis and caused severe proteinuria via nonepithelial, profibrotic effects on the kidney. The mechanisms involved in the aldosterone breakthrough phenomenon during ACEI and ARB therapy are still poorly understood. Clinical trial revealed that the urinary protein excretion, a major renal risk facor in patients with nephropathy, among patients experienced aldosterone breakthrough was much higher than among those who did not. However, aldosterone breakthrough has only been examined directly in small patients samples drawn from foreign patients.At present,there is no clear consensus on such key questions as how often breakthough occurs and whether breakthrough has clinical significance.ObjectiveThe aim of our study was to investigate the prevalence and impact of the aldosterone breakthrough during 6-month and 12-month ACEI/ARB treatment in Chinese patients with non-diabetic nephropathy.MethodsThe sample size was estimated before the study with the use of nQuery Adivisor software 6.0.According to the study of the treatment of patients with IgA nephropathy,the incidence of the aldosterone breakthrough was 53%. The calculated sample size of 125 patients was based on a two-sided significance level of 0.05, a statistical power of 80%, and a dropout rate of 20%.Patients with non-diabetic nephropathy from December 2008 to July 2009 from the cohort that consecutively attended renal outpatient and inpatient department of Nanfang Hospital and Zhujiang Hospital. This is a prospective, open-label, uncontrolled study, for a mean follow-up period of 12 months, including wash-out phase, run-in phase and follow-up phase.In the wash-out phase, all antihypertensive medication was withdrawn for at least 2 weeks.All patients enterd a four-week run-in phase during which they received 100 mg of losartan per day. To achieve a target blood pressure of below 130/80mmHg, we can increase the dose of losartan maximum to 200mg/d,if still did not achieve the target blood pressure,we can add benazepril maximum to 20mg/d;if still did not reach the target,we can added other antihypertensive treatment, i.e. calcium channel blockers and beta-blockers.In the follow-up phase, the antihypertensive treatment was the same as the end of run-in phase. Steroid or immunosuppressive therapy were prohibited throughout the study. At each clinic visit, physical examination, urinary protein, serum creatinine and potassium was measured. Study medication could be withheld in the event of serious hyperkalemia, dry cough, a serum creatinine concentration of increased 30% more than the baseline, a serum potassium concentration of more than 5.5mmol/l or intercurrent illness.All patients, however, remained in the study so that we could track hospitalizations and deaths. During treatment, all patients were instructed to restrict their salt and potassium intake.Baseline laboratory tests included a complete blood count, serum chemistry,24-h urinary protein excretion(UPE), peripheral plasma renin and plasma aldosterone concentrations(PAC). Peripheral plasma renin and PAC were determined before,6-month and 12-month after the therapy. Blood samples were taken, for measurement of plasma renin and PAC, by commercial radioimmunoassay, after the patients had been in the erect position for at least 2 hours.Statistical analysis:Data are expressed as mean±SD.Change in parameters in each group before and after treatment were compared by 2-group, paired t tests. Statistical significance was evaluated by 2-way ANOVA with repeated measures. The relationship between the reduction in protinuria and the decine in PAC and renal function was analyzed by Pearson correlation. Univariate test and multiple logistic regression models were use to explore the independent predictors of aldosterone breakthrough.A p value of less than 0.05 was considered significant(two-tailed test). SPSS software for Windows(version 13.0) was used for analyses.Results1.169 patients who met the inclusion criteria participated in the study,25 dropped out, seven because of adverse events.All statistical calculations were thus based on data generated from 144 patients(83 females and 61 males; aged 35.2±14.2 years;BMI 21.65±3.42 kg/m2, eGFR 59.18±22.02 ml/(min.1.73 m2)).2. After 12 months of treatment, proteinuria and mean aortie pressure (MAP) were reduced in all groups(P< 0.05), and the serum potassium level was slightly increased.The change in urinary protein in 12-month was higher than in 6-month (P=0.025), as well as the change in eGFR(P=0.002). 3. Aldosterone breakthrough was defined as an elevation of PAC after treatment of ACEI/ARB,compared with the pre-treatment value.Patients were divided into two groups according to the presence (breakthrough group) or absence (non-breakthrough group).In 6 months, aldosterone breakthrough occurred in 21 patients, corresponding to 14.58%; while in 12 months, occurred in 39 patients,corresponding to 27.08%, (P=0.009).4.82 patients were treated with Losartan, and 62 patients were treated with Benazepril and Losartan. The 6-month incidence of aldosterone breakthrough of the losartan group and the combined group was 15.85%(13/82) and 12.90%(8/62),(P=0.619). After 12 months of treatment, the plasma aldosterone increased in 20 patients in Losartan group (24.39%; aldosterone breakthrough), and 19 patients in combined group (30.65%; aldosterone breakthrough). There was no significant diffence between the the incidences of the two groups(P= 0.151). At the end of the study, the change of serum creatinine and eGFR were higher in the breakthrough group, and the change of UPE was lower in the breakthrough group.5. We divided all the patients into three groups according to eGFR:CKD-1 stage (40 patients), CKD-2 stage (53 patients),and CKD-3 stage(51 patients). The 6-month incidence of three groups was 7.50%(3/40),11.32%(6/53) and 23.52%(12/51),(P= 0.069), and the 12-month incidence was 15.00%(6/40), 24.53%(13/53) and 39.22%(20/51),(P= 0.031). The incidence of breakthrough raised with the increase of serum creatinine(P= 0.035). At the end of the study, the change of Scr and eGFR were higher in the breakthrough group, and the change of UPE was lower in the breakthrough group.6. The change in urinary protein was lower in the breakthrough group than the non-breakthrough group(P< 0.05).The median change of decline in eGFR during 6-month and 12-month of treatment was-1.24,-2.88 ml/(min.1.73m2) in breakthrough group, as compared with-0.56,-0.98 ml/(min.1.73m2) in the non-breakthrough group (P< 0.05).7. The change in Aldosterone was correlated with the change in Scr (r= 0.316, P< 0.001), the change in UPE(r= 0.441, P< 0.001), and the change in eGFR(r-0.282, P=0.001).8. Univariate logistic regression demonstrated that risk factors of aldosterone breakthrough included pre-treatment values of UPE (OR=3.643, P=0.073), and eGFR(OR=0.980, P=0.05). In multivariate logistic model, pre-treatment values of eGFR was an independent predictor of aldosterone breakthrough, with OR= 0.980,P=0.025.9. Adverse events:25 patients dropped out, two because of hyperkalemia and 2 because of dry cough. Postural hypotension occurred in 2 patients, and acute decline in renal function occurred in 1 patient. There was no report of Cardio-cerebral vascular events or death during the study.Conclusion1. Our study showed that aldosterone breakthrough during 6-month RASI blockade occurred in 14.58% of our patients with non-diabetic nephropathy, and 27.08% in 12-month treatment.2. The study revealed that treatment value of UPE was higher in patients with aldosterone breakthrough.Aldosterone breathrough during 12-month treatment was associated with an enhanced decline in eGFR in patients with non-diabetic CKD.3. Pre-treatment values of eGFR was independent risk factor of aldosterone. |
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