Febuxostat for hyperuricemia in patients with advanced chronic kidney disease.

Febuxostat is a nonpurine xanthine oxidase (XO) inhibitor, which recently received marketing approval. However, information regarding the experience with this agent among advanced chronic kidney disease (CKD) patients is limited. In the current study, we investigated the effects of oral febuxostat in patients with advanced CKD with asymptomatic hyperuricemia. We demonstrated, for the first time, that not only the serum levels of uric acid (UA) but also those of 8-hydroxydeoxyguanosine, an oxidative stress marker, were significantly reduced after six months of febuxostat treatment, with no adverse events. These results encouraged us to pursue further investigations regarding the clinical impact of lowering the serum UA levels with febuxostat in advanced CKD patients in terms of concomitantly reducing oxidative stress via the blockade of XO. More detailed studies with a larger number of subjects and assessments of the effects of multiple factors affecting hyperuricemia, such as age, sex, and dietary habits, would shed light on the therapeutic challenges of treating asymptomatic hyperuricemia in patients with various stages of CKD.

Action of irbesartan on blood pressure and glucose/lipid metabolism, in hemodialysis patients with hypertension.

BACKGROUND: Irbesartan has been reported to have beneficial effects on glucose/lipid metabolism in addition to an antihypertensive effect; however, such effects have not been clarified in hemodialysis (HD) patients. We investigated the effects of irbesartan on blood pressure (BP) as well as glucose/lipid metabolism, in HD patients with hypertension. METHODS: Seventeen HD patients with hypertension, aged 62.7 ± 12.5 years, were treated with daily oral administration of 50 to 100 mg of irbesartan for 12 weeks. Then, the changes of BP as well as glucose metabolism (random serum glucose level and serum glycosylated hemoglobin [HbA1c] level) and lipid metabolism (serum low-density lipoprotein cholesterol [LDL-chol] level, serum high-density lipoprotein cholesterol [HDL-chol] level, and serum triglyceride [TG] level) were evaluated. RESULTS: Irbesartan significantly reduced systolic BP (154.9 ± 12.8 to 139.4 ± 13.1 mmHg (P < 0.01) and diastolic BP (78.9 ± 9.1 to 72.2 ± 9.7 mmHg, P < 0.01). It also reduced LDL-chol (77.6 ± 19.1 to 72.0 ± 18.6 mg/dL, P < 0.05), whereas it did not significantly affect random serum glucose (129.3 ± 46.9 mg/dL to 130.6 ± 47.2 mg/dL), HbA1c (5.58% ± 1.41% to 5.49% ± 1.11%), TG (104.3 ± 65.8 mg/dL to 100.2 ± 59.9 mg/dL), or HDL-chol (44.8 ± 17.1 mg/dL to 45.7 ± 15.6 mg/dL). CONCLUSION: Irbesartan is effective for BP control and may have beneficial effects on lipid metabolism in HD patients.

Long-term effects of aliskiren on blood pressure and the renin-angiotensin-aldosterone system in hypertensive hemodialysis patients.

OBJECTIVE: The long-term effects of aliskiren in hypertensive hemodialysis patients remain to be elucidated. DESIGN: In this post hoc analysis, we followed up 25 hypertensive hemodialysis patients who completed 8-week aliskiren treatment in a previous study for 20 months to investigate the blood pressure-lowering effect and inhibitory effect on the renin-angiotensin-aldosterone system. RESULTS: Among the 25 patients, eleven patients continued with aliskiren treatment. Blood pressure (± standard deviation) decreased from 175 ± 18/80 ± 11 mmHg at baseline to 156 ± 20/76 ± 9 mmHg at month 20. Plasma renin activity, angiotensin I, and angiotensin II decreased from baseline to month 20 (plasma renin activity (ng/mL/h): 2.3 ± 2.6 to 0.3 ± 0.4 (P < 0.05), angiotensin I (pg/mL): 909.1 ± 902.5 to 41.5 ± 14.8 (P < 0.05), angiotensin II (pg/mL): 41.5 ± 45.8 to 11.0 ± 4.9 (P < 0.05)). CONCLUSION: Long-term treatment with aliskiren provides effective blood pressure lowering and inhibition of the renin-angiotensin-aldosterone system, which are sustained over 20 months in hypertensive hemodialysis patients.

The association of plasma prorenin level with an oxidative stress marker, 8-OHdG, in nondiabetic hemodialysis patients.

BACKGROUND: Circulating prorenin contributes to the pathogenesis of tissue damage leading to cardiovascular disease (CVD) in hypertension and diabetic mellitus (DM) by activating the tissue renin-angiotensin-aldosterone (RAS) system; however, little is known about its roles in hemodialysis (HD) patients. METHODS: We evaluated plasma prorenin level and prorenin receptor [(P)RR] expression in peripheral blood mononuclear cells (PBMCs) in 49 nondiabetic HD (non-DM-HD) patients. Then we investigated the association between plasma prorenin level or (P)RR expression level in PBMCs and CVD-predictive biomarkers. RESULTS: The plasma prorenin level increased in non-DM-HD patients [147.1 ± 118.9 pg/ml (standard value <100 pg/ml)]. The (P)RR mRNA expression level in PBMCs also increased 1.41 ± 0.39-fold in non-DM-HD patients compared with that in healthy control subjects (p < 0.001). Although plasma prorenin level did not correlate with plasma BNP level and plasma high-sensitivity C-reactive protein level, it significantly correlated with plasma 8-hydroxydeoxyguanosine (8-OHdG) level (r = 0.535, p < 0.001). The plasma prorenin level did not correlate with plasma renin activity (PRA), plasma angiotensin I (AT I) level, plasma angiotensin II (AT II) level and plasma aldosterone (Ald) level. PRA, plasma AT I level, plasma AT II level and plasma Ald level did not correlate with the level of any CVD predictive biomarker. (P)RR expression level in PBMCs did not correlate with the level of any CVD predictive biomarker. CONCLUSIONS: The plasma prorenin level and (P)RR expression level in PBMCs increased, and the plasma prorenin level was associated with plasma 8-OHdG level independent of circulating RAS in non-DM-HD patients.

Effects of aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysis-dependent chronic kidney disease patients with hypertension.

The renin-angiotensin-aldosterone system (RAAS) has pivotal roles in the pathogenesis of hypertension in hemodialysis-dependent chronic kidney disease (HDD-CKD) patients. Activated RAAS also increases inflammatory mediators by directly increasing proinflammatory gene expression and by putting oxidative stress on the vascular endothelium. Both hypertension and inflammation are major risk factors for cardiovascular disease (CVD) in HDD-CKD patients. In this study, we assessed the efficacy of a direct renin inhibitor, aliskiren, on blood pressure (BP) and CVD predictive biomarkers, such as brain natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP) and diacron-reactive oxygen metabolite (d-ROM). A total of 30 hypertensive HDD-CKD patients were assigned to receive aliskiren (150 mg) orally once daily with their existing antihypertensives. After 8 weeks, aliskiren treatments reduced systolic blood pressure (SBP) from 169.0±20.1 to 153.7±19.6 mmHg (P<0.001) and diastolic blood pressure (DBP) from 78.1±12.0 to 73.0±13.6 mmHg (P=0.048). RAAS was suppressed by aliskiren treatment as follows: PRA (from 3.6±4.0 to 1.0±1.5 ngml(-1)h(-1) (P=0.004)), angiotensin I (from 1704.0±2580.9 to 233.7±181.0 pgml(-1) (P=0.009)), angiotensin II (from 70.2±121.5 to 12.4±11.5 pgml(-1) (P=0.022)) and aldosterone (from 107.9±148.0 to 73.1±34.6 pgml(-1) (NS)). The biomarkers for CVD were inhibited by aliskiren: BNP (from 362.5±262.1 to 300.0±232.0 pgml(-1) (P=0.043)), hS-CRP (from 6.2±8.1 to 3.5±3.7 mgl(-1) (P=0.022)) and d-ROM (from 367.0±89.8 to 328.3±70.9 U.CARR (P=0.022)). The inhibition levels of biomarkers for CVD by aliskiren did not correlate with the decreased levels of SBP and DBP. These results suggested that aliskiren was effective for BP control and may have cardiovascular protective effects in hypertensive HDD-CKD patients.