Hiroshi Takane

Comparison of the Effects of Angiotensin Receptor Antagonist, Angiotensin Converting Enzyme Inhibitor, and their Combination on Regression of Left Ventricular Hypertrophy of Diabetes Type 2 Patients on Recent Onset Hemodialysis Therapy

Abstract:  Left ventricular hypertrophy (LVH) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients, and is highly predictive of future cardiac morbidity and mortality. In patients with hypertension and LVH, both an angiotensin converting enzyme (ACE) inhibitor and an angiotensin type 1 receptor (AT1) antagonist regress LVH. However, it remains controversial whether dual blockade of the renin–angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist. Thirty‐three type II diabetic patients with end‐stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School, Saitama, Japan between 1999 and 2001. The study was carried out for 1 year. All patients were assigned randomly to three groups with equal number: group I, an ACE inhibitor, enalapril 10 mg daily; group II, an AT1 antagonist, losartan 100 mg daily; group III, combination of enalapril 10 mg and losartan 100 mg daily. All antihypertensive drugs were given 30 min after the cessation of dialysis therapy. LVH was evaluated by echocardiography before the start of administration of drugs, at 6 months and 12 months after the start of drug therapy. Systolic blood pressure levels less than 140 mmHg were the target for the three groups. Using repeated measures analysis of variance, applied to those with four echocardiograms, there were progressive decreases over time in left ventricular mass index, posterior wall thickness and interventricular septum thickness. There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups; however, dual blockade induced an additional 28% reduction in left ventricular mass index compared with any type of monotherapy. Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy. Moreover, combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy.

Angiotensin receptor antagonist regresses left ventricular hypertrophy associated with diabetic nephropathy in dialysis patients.

Background Left ventricular hypertrophy (LVH) is frequently found at the initiation of dialysis therapy for diabetic and hypertensive patients, and is highly predictive of future cardiac morbidity and mortality. Angiotensin type 1 receptor (AT1) antagonists may be able to regress LVH by mechanisms independent of their antihypertensive effects in diabetic patients. It is not known whether AT1 antagonists are able to reverse LVH in diabetic patients on dialysis therapy. Method Twenty-four type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy, and were diagnosed as having LVH evaluated by echocardiography, were selected from 3 dialysis units staffed by the faculty of Saitama Medical School between 1998 and 2001. The study was carried out for 1 year. All patients were randomly assigned to 2 groups. One group received an AT 1 antagonist, losartan 100 mg daily 30 minutes after the cessation of dialysis therapy on dialysis days, or in the evening when dialysis therapy did not occur. The control group received placebo. LVH was evaluated by echocardiography before the start of administration of drugs, at 4 and 8 months, and again at 12 months after the start of drug therapy. A systolic blood pressure of less than 140 mm Hg was the target blood pressure in both groups. Results Using repeated measures analysis of variance, applied to those with 4 echocardiograms, there were progressive decreases over time in the left ventricular mass index (LVMi), posterior wall thickness, and intraventricular wall thickness in patients receiving losartan. The biggest changes in mass and the other parameters occurred between baseline and at month 6. Compared with these changes in the patients receiving losartan, left ventricular internal diameters and their derived parameters (e.g., ejection fraction) remained unchanged throughout the study. In spite of a similar reduction of bp in the patients receiving placebo, no significant changes in echocardiographic parameters were found in these patients. Conclusion An AT 1 antagonist, losartan, is beneficial for the regression of LVH in diabetic patients who started dialysis therapy under adequate blood pressure control.

Long-Term Effects of Calcium Antagonists on Augmentation Index in Hypertensive Patients with Chronic Kidney Disease: A Randomized Controlled Study

Background: Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD). Methods: The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure. Results: Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 ± 1 vs. –2 ± 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group (–29 ± 2 vs. –38 ± 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (–4 ± 1 vs. –9 ± 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period. Conclusion: In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection.

Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney diseases

Sir, In 2004, the Japanese Society of Hypertension recommended calcium channel blockers (CCBs) as second line drugs, with the renin–angiotensin (Ang) system (RAS) inhibitor as the first choice, for the treatment of hypertension associated with chronic kidney disease (CKD). We reported that augmentation index (AI) is related to proteinuria in CKD patients, and that RAS inhibition preserves arterial compliance in CKD [1,2]. However, the effects of CCBs on arterial stiffness remain unclear among CKD patients. A prospective comparative study was performed between 26 non-diabetic CKD patients treated with amlodipine and 27 patients on benidipine (supplemental methods). Patient backgrounds including the prescription of the RAS inhibitor did not differ between groups (supplemental table). Brachial blood pressure was controlled equally well in both groups for a year (supplemental figure). A year later, body weight (to 59 ± 11 kg, P < 0.05) and estimated glomerular filtration rate (eGFR) were decreased, and AI was increased without changes in proteinuria (Figure ​(Figure1)1) in the amlodipine group. However, in the benidipine group, either eGFR, body weight or AI was not altered, but proteinuria was reduced. Fig. 1 Annual changes in urinary protein (UP, left panel), estimated glomerular filtration rate (eGFR, middle panel) and augmentation index (AI, right panel). *P < 0.05 from zero. Significant decreases in UP (116 ± 93 to 82 ± 67 mg/g ... In renal tissue, L-type calcium channels are only found in afferent arterioles, while N-type and T-type calcium channels are localized in both afferent and efferent arterioles [3]. Amlodipine blocks L-type and N-type calcium channels and dilates afferent arterioles much more than efferent arterioles. In contrast, benidipine that inhibits L-type and T-type calcium channels, dilates both afferent and efferent arterioles and reduces glomerular pressure. We have demonstrated that efferent arteriolar constriction is mediated by inositol trisphosphate-induced calcium mobilization and calcium entry through transient receptor potential (TRP) channels [4]. T-type CCBs inhibited AngII-induced calcium mobilization rather than calcium entry in efferent arterioles [3]. TRP channels possess molecular similarity with voltage-dependent calcium channels, but they lack the structure of voltage-sensor, gating independently of voltage. It is possible that some CCBs including benidipine inhibit calcium entry through TRP channels into efferent arteriole. Increasing AI elevates central blood pressure, worsening glomerular hypertension, proteinuria, renal and cardiovascular prognosis [1,2]. Although we would not deny the other possibilities (supplemental discussion), benidipine could reduce oxidative stress on arterial wall by decreasing proteinuria. Albumin passed through slit diaphragm is absorbed by proximal tubular cells. Although a small amount of protein is cleaved by acidification [5], oxidative process is involved in dealing a large amount of protein, generating reactive oxygen species that appear to leak from the kidney. This escalation of AI should worsen glomerular hypertension further, forming a vicious circle of progressive kidney damage [1,2]. Our results provided the evidence that benidipine may be superior to amlodipine in renoprotection as the antihypertensive additional to the RAS inhibitor when similar blood pressure levels are attained. Furthermore, the present data suggest that the influence on AI differs among types of CCBs in patients with CKD. Conflict of interest statement. None declared.

Seasonal Variations of Daily Changes in Blood Pressure Among Hypertensive Patients with End-Stage Renal Diseases

Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension, and their blood pressure elevates in winter. However, seasonal changes in daily variations of blood pressure are poorly assessed in patients treated with hemodialysis. Thirty hypertensive patients with end-stage renal diseases were enrolled in the study. Dry weight and antihypertensive medications were altered when they were necessary. Home blood pressure measurements were performed at least for 1 week in each season; April–May 2008, July–August 2008, October–November 2008, and January–February 2009. Both morning and evening systolic blood pressures (SBPs) showed significant seasonal changes ( p < 0.01), with the highest blood pressure in winter (162 ± 18 and 135 ± 22 mmHg in morning and evening). Morning diastolic blood pressure (DBP) also exhibited seasonal changes ( p < 0.05), with the highest blood pressure in fall ( 78 ± 8 mmHg). Evening DBP did not manifest seasonal deviations. Morning-evening differences in SBP and DBP were the greatest in winter (28 ± 21 and 10 ± 9 mmHg in SBP and DBP, p < 0.01), and the smallest in summer (16 ± 12 and 6 ± 5 mmHg). Daily variations of SBP and DBPs in spring (19 ± 12 and 7 ± 6 mmHg) and fall (20 ± 13 and 9 ± 8 mmHg) were between those of summer and winter. Our results indicate that not only averaged blood pressure but also variations of blood pressure in winter are larger than the other seasons, and suggest that these blood pressure variations participate in cardiovascular events in hypertensive patients with end-stage renal diseases.

Validation of carotid blood pressure assessment by tonometry.

T he authoritative review on microvascular brain damage with aging supplements the excellent session on the topic addressed by Scuteri et al. [1] at the 2011 European Society of Hypertension meeting in Milan. The authors referred to two hypotheses to explain underlying mechanism of microvascular damage: one advanced by us (their reference 18), attributing this to high pulsatile flow and longitudinal shear stress caused by aortic stiffening and early wave reflection, and the second which attributed damage to reduction in diameter of the aorta and large arteries with microvascular ‘remodelling’. We are uncomfortable with the second (alternate) hypothesis (authors references 24, 25), because the fundamental views on aortic narrowing with age were based on indirect measures and have been seriously challenged [2,3]. Views on ‘remodelling’ suggest compensatory processes (rather than physical damage, as suggested by us on the basis of the established long-accepted work of Byrom [4] and Fry [5]). Thickening of the arteriolar wall and luminal narrowing are explained by both hypotheses and could further increase pulsatile shear and wall damage. The authors hypothesize that such arterial narrowing is compensatory and serves to protect the microvasculature; this view is hard to maintain when similar luminal changes are seen in the veins further downstream. We congratulate the authors on a splendid document which draws attention to unresolved problems in prevention and management of stroke. We hope the comments offered here provide some insight into the only issue that we consider contentious. The principal issue is ‘can a condition which alters normal vascular morphology and function, and causes dementia, be considered ‘adaptation’.

Aliskiren Reduces Morning Blood Pressure in Hypertensive Patients with Diabetic Nephropathy

Diabetic nephropathy (DN) is a leading disease that requires renal replacement therapy. The progression of renal dysfunction in DN is faster than the other renal diseases. While antihypertensive therapy reduces albuminuria, a good indicator for the progression, hypertension in DN is treatment resistant. Among patients with DN who took angiotensin receptor blockers (ARBs), 27 patients who exhibited poor control of albuminuria were enrolled into the study. Angiotensin receptor blocker was exchanged to aliskiren (150–300 mg/d) and clinical parameters were followed for 6 months. Exchange to aliskiren decreased albuminuria (1.57 ± 0.68 to 0.89 ± 0.45 g/gCr, P < .01) without changes in estimated glomerular filtration rate and office blood pressure (BP). Body weight and hemoglobin A1c were not altered. Aliskiren also reduced plasma renin activity (2.0 ± 0.9 to 1.2 ± 0.6 ng/mL/h, P < .01). While evening BP was unchanged, morning systolic BP (139 ± 8 to 132 ± 7 mm Hg, P < .01) and diastolic BP (81 ± 7 to 76 ± 6 mm Hg, P < .05) were decreased significantly after 6 months. Our results indicated that aliskiren decreased BP, especially morning BP in hypertensive patients with DN. The present data suggest that aliskiren exerts renoprotective actions including reduction in albumin excretion for patients with DN.

Height constitutes an important predictor of mortality in end-stage renal disease.

Aim. Height is an important determinant of augmentation index (AI) that anticipates cardiovascular prognosis. There is a scanty of the data whether short height predicts survival in patients with end-stage renal diseases, a high risk population. Methods. Fifty two hypertensive patients with type 2 diabetic nephropathy receiving hemodialysis and 52 patients with nondiabetic nephropathy were enrolled. In addition to AI estimated with radial artery tonometry, classical cardiovascular risk factors were considered. Patients were followed for 2 years to assess cardiovascular prognosis. Results. Cox hazards regression revealed that both smoking and shortness in height independently contributed to total mortality and indicated that smoking as well as the presence of left ventricular hypertrophy predicted cardiovascular mortality. Our findings implicated that high AI, the presence of diabetes, and low high-density lipoprotein cholesterol were significant contributors to cardiovascular events. Conclusions. Our findings provide new evidence that shortness in height independently contributes to total mortality in hemodialysis patients.

Statin Improves Flow-Mediated Vasodilation in Chronic Kidney Diseases

Background. Numbers of drugs are required to manage patients with chronic kidney disease (CKD). Drug adherence is relatively poor in this population. Methods. In 36 CKD patients with hypertension and dyslipidemia, who were prescribing amlodipine 5 mg and atorvastatin 10 mg daily, the influences of exchanging to a combination drug containing equivalent doses of amlodipine and atorvastatin were observed for 6 months. Results. At the baseline, flow-mediated dilation (FMD) was reduced (2.4 ± 0.3%), and proteinuria was significantly contributed to decrements of FMD (R 2 = 0.38, F = 3.7, df (6,29), and  P < 0.01). Six months later from exchanging to combination drug, total cholesterol (TC, 197 ± 5 to 183 ± 3 mg/dL,  P < 0.01) and triglycerides (142 ± 14 to 129 ± 10 mg/dL, P < 0.05) were decreased, but high density lipoprotein cholesterol (53 ± 3 to 56 ± 3 mg/dL, P < 0.05) was increased. FMD was slightly albeit significantly improved to 2.7 ± 0.3% (P < 0.05). No serious adverse effects were seen by the combination drug. Subanalysis for the patients with considerable reductions of TC demonstrated that the combination drug decreased proteinuria and high sensitive CRP (P < 0.05 for both). Conclusion. Our data indicate that proteinuria constitutes a determinant of a reduced FMD. The present results implicate that combination drug is useful to improve adherence and suggest that atorvastatin refines endothelium function as well as lipid profiles in CKD patients.

Zigzagged Augmentation Index in Diabetes

Although the patients with diabetic nephropathy suffered high cardiovascular risk, augmentation index (AI) in diabetic nephropathy has been poorly characterized. Cross-sectional studies were performed on 26 diabetic and 27 nondiabetic nephropathic patients. Home blood pressure was examined. In addition, blood pressure, pulse rate, and AI were measured in both supine and sitting positions. Patient backgrounds such as age, sex, sitting blood pressure, and pulse rate were similar between two groups. Circadian variations of home blood pressure were preserved in nondiabetic patients, but disappeared in diabetes. Changing from supine to sitting position induced greater decrements of systolic blood pressure (ΔSBP −9 ± 8 mmHg) and AI (ΔAI −7 ± 10) in the diabetic group than in nondiabetic patients (ΔSBP −4 ± 12 mmHg, ΔAI −2 ± 9). Multivariate regression analysis revealed that AI in a sitting position correlated positively to SBP and inversely to pulse rate. Of interest, AI in supine position related positively to age, the presence of diabetes and SBP, and inversely to pulse rate. The present data indicate autonomic dysfunction in patients with diabetic nephropathy. Furthermore, our findings provide the evidence that autonomic dysfunction elicits an inadequate physiological arterial contraction in response to postural change, thereby reducing AI that results in the fall of SBP. Finally, the present results suggest that AI in supine, but not sitting position, is suited for detecting cardiovascular risk in diabetes.