Vascular Endothelial Growth Factor-A Increases the Aqueous Humor Outflow Facility.

PURPOSE: Anti-vascular endothelial growth factor (VEGF) antibody therapy is an effective treatment for ocular angiogenesis. Although the intraocular pressure of some patients increases after anti-VEGF therapy, the effects of VEGF-A on the aqueous humor outflow pathway remain unknown. This study investigated the effects of VEGF-A on the aqueous humor outflow pathway. METHODS: We used human recombinant VEGF121 and VEGF165. Trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells were isolated from the eyes of cynomolgus monkeys. Expression of mRNA coding four VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), neuropilin-1, and neuropilin-2, was examined by RT-PCR. To evaluate the permeability of cell monolayers, we measured transendothelial electrical resistance (TEER). The outflow facility was measured in perfused porcine anterior segment organ cultures treated with 30 ng/mL VEGF121 for 48 h. RESULTS: Four VEGF-A-related receptor mRNAs were expressed in TM and SCE cells. The TEER of TM cells was not significantly affected by VEGF121 or VEGF165 treatment. In contrast, the TEER of SCE cells was significantly lower 48 h after treatment with 30 ng/mL VEGF121 to 69.4 ± 12.2% of baseline (n = 10), which was a significant difference compared with the control (P = 0.0001). VEGF165 (30 ng/mL) decreased the TEER of SCE cells at 48 h after treatment to 72.3 ± 14.1% compared with the baseline (n = 10), which was not a significant difference compared with the control (P = 0.0935). Ki8751, a selective VEGFR2 inhibitor, completely suppressed the effect of VEGF121 on SCE cell permeability, although ZM306416, a selective VEGFR1 inhibitor, did not affect the VEGF121-induced decrease in TEER. Perfusion with 30 ng/mL of VEGF121 for 48 h significantly increased the outflow facility compared with the control (47.8 ± 28.5%, n = 5, P = 0.013). CONCLUSIONS: These results suggest that VEGF-A may regulate the conventional aqueous outflow of SCE cells through VEGFR2.

[Effect of an educational admission program for patients at the conservative phase of chronic kidney disease (CKD)].

PURPOSE: We have been conducting a 1-week educational admission program for patients at the conservative phase of chronic kidney disease (CKD) since 2006. In this study we evaluated the effect of the program. METHODS: We retrospectively reviewed 469 patients who could be followed for 12 months after a 1-week educational admission program for CKD out of a total of 700 patients who attended the program between October 2006 and April 2012. We compared the rates of decrease in renal function before and after the program. In addition, we divided the patients into two groups of diabetic nephropathy and non-diabetic nephropathy. We compared the rate of decrease in renal function in each group. RESULTS: The rate of decrease in renal function 12 months after discharge was improved compared with that 6 months before admission. (before: 0.316 mL/min/1.73 m2/month; after: 0.001 mL/min/1.73 m2/month.) The rate of decrease in renal function 6 months before admission of the diabetic nephropathy group was 72.3 times faster than that of the non-diabetic nephropathy group. However, the rate of decrease in renal function 12 months after admission was improved in both groups. CONCLUSION: It was revealed that the educational admission program is effective for preserving the renal function on patients at the conservative phase of CKD.

[Case of fanconi syndrome positive for anti-M2 antibodies revealed by severe hypokalemia and multiple bone fracture].

A 38-year-old female developed pain in the right leg in 2006. In 2007, the diagnosis of femoral head necrosis was made based on MR images, and femoral head prosthetic replacement was performed. In April 2009, she visited a local hospital for low back pain, and was referred to our department due to electrolyte abnormalities on hemanalysis. Since marked hypokalemia (K=2.5 mEq/L), hypophosphatemia, hyperchloric metabolic acidosis, proteinuria, and urinary blood sugar suggested Fanconi syndrome, she was admitted for close examination. Bone survey showed a marked decrease in the amount of bone particularly in the four limbs and fracture at the proximal 1/3 of the left ulnar bone. In the lumbar spine, scoliosis and vertebral deformity were observed. Since impaired P re-absorption and unselected aminoaciduria and osteomalacia were also present, the diagnosis of Fanconi syndrome was made. On admission, ventricular tachycardia developed due to hypokalemia, requiring immediate electrolyte correction. For differentiation from acquired Fanconi syndrome, various examinations were performed. No apparent cause was found except for the positive antimitochondrial antibody-M2 (anti-M2). In this case, no data suggested liver dysfunction, and subsequent liver biopsy also showed no significant pathological findings pointing to PBC. We encountered a patient with Fanconi syndrome positive for anti-M2. This case may attract interest, particularly in the mechanism of nephropathy due to anti-M2, and therefore, this case is reported with a literature review.

Characteristics of 20-year survivors undergoing maintenance hemodialysis.

Hemodialysis techniques have improved remarkably in recent decades and the number of long-term survivors among patients with end-stage renal disease has increased. The mortality rate of hemodialysis patients has been reported to be low in Japan. However, the long-term survival rate of dialysis patients is still low: 23.6% for 15 years and 17.4% for 20 years, even in Japan, and background information on patients undergoing hemodialysis therapy for more than 20 years is scarce in this country. In the present study, we investigated the characteristics of 20-year survivors undergoing maintenance hemodialysis at our medical center. We compared the characteristics of hemodialysis patients who had survived for more than 20 years after the initiation of hemodialysis with those of patients who started hemodialysis at the same time and had already died. No patient among those who were still alive had diabetes mellitus while 15% of patients who had died had diabetes mellitus at the time of initiation of hemodialysis. Age, cardiothoracic ratio, and serum levels of total cholesterol and triglyceride 6 months after the initiation of hemodialysis, as well as decreases in body weight per year were significantly lower in those who had survived than in those who had died. These results suggest that long-term hemodialysis survivors are characterized by (i) initiation of hemodialysis at a young age (ii) being free of diabetes mellitus (iii) a well-controlled cardiothoracic ratio (iv) small successive change in body weight, and (v) being free of hypercholesterolemia and hypertriglyceridemia.

Successful permanent catheter implantation after percutaneous transluminal angioplasty to the right subclavian and inominate vein stenosis in a hemodialysis patient.

Difficulties in gaining vascular access have become one of the major problems in long-term hemodialysis patients. We report a case with an extreme vascular access problem, which was solved by the placement of a permanent central vein catheter after successful angioplasty to the right subclavian and inominate vein stenosis. A 78-year-old woman with end-stage renal disease due to diabetic nephropathy had been on hemodialysis since 1982. She had a history of four procedures that created an arteriovenous fistula during the first four years. In 1986 she was switched to peritoneal dialysis. However, hemodialysis was restarted with a regular arteriovenous fistula in 1991 because of repeated peritonitis, and from 1993 a superficialized brachial artery was used until the artery was exhausted. Since 1997, a permanent central vein catheter was utilized and reinsertion was required four times due to catheter infection during a 6-year period. In 2004, difficulty was experienced in reinserting a new central venous catheter because of multiple stenotic and occlusive lesions of the central veins. Percutaneous transluminal angioplasty was carried out in the stenotic right subclavian and inominate veins, and after successful angioplasty, a permanent central vein catheter could be placed into the right subclavian vein as a vascular access for hemodialysis. Pretreatment with percutaneous transluminal angioplasty of the stenotic central veins before inserting a permanent catheter may be a useful strategy in patients that experience difficulty in the insertion of a catheter.

Risk factors of normal ankle-brachial index and low toe-brachial index in hemodialysis patients.

The prevalence of peripheral arterial occlusive disease is high in patients with terminal renal failure, and it is a major problem in those on dialysis. A low ankle-brachial index (ABI) suggests the presence of arterial stenotic lesions between the aorta and the ankle joint, while a low toe-brachial index (TBI) suggests stenotic lesions between the aorta and the toes. Therefore, a normal ABI (> or =0.9) and a low TBI (<0.6) may indicate the presence of stenotic lesions located only on the peripheral side of the ankle joint. In the present study, risk factors of normal ABI/low TBI were investigated. In 115 patients on maintenance dialysis, the ABI and TBI were simultaneously measured, and the background factors and laboratory data of patients with normal ABI/low TBI (L group) and those with normal ABI/normal TBI (> or =0.6) (N group) were compared. Low ankle-brachial and toe-brachial indices were detected in 13% and 22% of the patients, respectively. Comparison of the background factors and laboratory data between the N and L groups showed that the ratio of diabetes mellitus, interdialytic body weight gain, and Hb(A1c) values were significantly higher in the L group than in the N group. It was clarified that diabetes and excess body weight gain are involved as risk factors in dialysis patients with normal ABI/low TBI.

Prognostic significance of ankle-brachial index, brachial-ankle pulse wave velocity, flow-mediated dilation, and nitroglycerin-mediated dilation in end-stage renal disease.

BACKGROUND: Identifying patients at high risk of cardiovascular disease is important in managing patients undergoing hemodialysis. METHODS: We evaluated a series of prognostic values: flow-mediated dilation (FMD) and nitrogen-mediated dilation (NMD), an index of endothelium-dependent and endothelium-independent function, respectively, ankle-brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV) in patients undergoing chronic hemodialysis. RESULTS: A cohort of 199 patients was studied. At entry, these values were examined and the prognostic significances were investigated. In estimating the significance of baPWV, patients with ABI <0.9 were excluded. During the follow-up period, 24 deaths occurred including 14 cardiovascular and 10 noncardiovascular fatal events. Overall, the survival rates were significantly lower in the low ABI than in the high ABI group, but the survival rates were not significantly different between the high and low FMD, NMD, or baPWV groups. Cardiovascular survival rates were significantly lower in the low ABI than in the high ABI group, and in the high baPWV than in the low baPWV group. The survival rates were not significantly different between the high and low FMD or NMD groups. CONCLUSIONS: Screening hemodialysis patients by means of ABI and baPWV but not FMD or NMD provides complementary information in identifying a high-risk population in these patients.

Effects of efonidipine hydrochloride on heart rate and circulatory changes due to stress.

Efonidipine hydrochloride is a dual Ca channel blocker that inhibits T-type Ca channels, which are localized in the sinoatrial node and are involved in the pacemaker mechanism of the heart, as well as L-type Ca channels. In the present study, the effect of efonidipine hydrochloride in inhibiting an increase in heart rate along with changes in circulation during mental and physical stress was examined using normotensive volunteers. A mental arithmetic test caused significant increases in heart rate and blood pressure, which were significantly inhibited 3 hours after oral administration of 40 mg of efonidipine hydrochloride but not at 1 week after cessation of administration. In contrast, the plasma norepinephrine, epinephrine, renin activity, and aldosterone levels following the test were unchanged at both 3 hours and 1 week after administration of efonidipine hydrochloride. Physical stress in the form of cold by immersing one hand in ice water for 2 minutes induced similar increases in the heart rate and blood pressure, which were significantly reduced at 3 hours but not at 1 week after administration of efonidipine hydrochloride. The plasma levels of the humoral factors previously described following the physical stress were unchanged at either 3 hours or 1 week after administration of efonidipine hydrochloride. These results suggest that efonidipine hydrochloride inhibits increases in heart rate and blood pressure due to stress, presumably by blocking T-type Ca channels rather than by inhibiting the sympathetic nervous system. Therefore, efonidipine hydrochloride is expected to be a Ca antagonist that exhibits a strong cardioprotective effect.

Beneficial effects of combination therapy with angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor on vascular endothelial function.

The combination of angiotensin I-converting enzyme inhibitors and angiotensin receptor blockers has been shown to be more effective than the individual drugs alone in the treatment of chronic kidney disease and chronic heart failure. In the present study, we evaluated the effect of treatment with the calcium channel blocker amlodipine or the angiotensin I-converting enzyme inhibitor perindopril on vascular endothelial function and arteriosclerosis in patients with essential hypertension who had already been receiving angiotensin receptor blocker monotherapy. Thirty-two patients with essential hypertension treated with angiotensin receptor blocker monotherapy were randomized to receive 5 mg of amlodipine (n=16) or 4 mg of perindopril (n=16) once daily in the morning for 24 weeks. The patients were evaluated before and after therapy to assess changes in blood pressure, flow-mediated vasodilation (a parameter of vascular endothelial function), and brachial-ankle pulse wave velocity (a parameter of arteriosclerosis). Before treatment, there were no significant differences in the above parameters between groups. After treatment, there was a similar significant decrease in blood pressure in both groups. Flow-mediated vasodilation increased significantly in the perindopril group compared with the amlodipine group; however, the decrease in brachial-ankle pulse wave velocity was not significantly different between groups. In conclusion, these results suggest that the angiotensin I-converting enzyme inhibitor perindopril is superior to the calcium channel blocker amlodipine for reducing vascular endothelial dysfunction when co-administered with angiotensin receptor blockers in patients with essential hypertension.

Renal and vascular protective effects of cilnidipine in patients with essential hypertension.

OBJECTIVES: Cilnidipine is a calcium channel blocker that blocks both L and N-type calcium channels. L/N-type calcium channel blockers exhibit sympatholytic action and a renal protective effect via dilation of afferent and efferent arterioles of the renal glomerulus, and afford more potent protection against hypertension-related organ damage than L-type calcium channel blockers. Few studies, however, have directly compared the organ protective effects of L-type calcium channel blocker monotherapy and L/N-type calcium channel blocker monotherapy. This study compares the effects on renal and vascular endothelial functions and arterial stiffness of monotherapy regimens of amlodipine, an L-type calcium antagonist, and cilnidipine, in patients with essential hypertension. METHODS: Fifty patients with untreated essential hypertension were randomized to receive 5 mg of amlodipine (n = 25) or 10 mg of cilnidipine (n = 25) once daily in the morning for 24 weeks. The patients were evaluated before and after the therapy to assess changes in renal function, flow-mediated vasodilation (a parameter of vascular endothelial function), and brachial-ankle pulse wave velocity (a parameter of arterial stiffness). RESULTS: Before treatment, the above parameters showed no significant differences between groups. After treatment, urinary albumin excretion was decreased significantly in the cilnidipine group compared with the amlodipine group, and the decrease of brachial-ankle pulse wave velocity was significantly larger in the cilnidipine group than in the amlodipine group. CONCLUSIONS: These results suggest that cilnidipine is more effective than amlodipine at improving renal function and arterial stiffness in patients with essential hypertension.

Efficacy of low-density lipoprotein apheresis in patients with peripheral arterial occlusive disease undergoing hemodialysis treatment.

BACKGROUND: Low-density lipoprotein (LDL) apheresis is effective in the treatment of peripheral arterial occlusive disease (PAOD). In the present study, we attempted to determine whether LDL apheresis is effective even for PAOD patients undergoing hemodialysis, who tend to be refractory to any treatment, and if so, to determine the mechanism of its efficacy. METHODS: Serum levels of lipids and vascular growth factors, leg symptom, and endothelium-dependent vasodilation were investigated before and after 10 sessions of LDL apheresis in 11 PAOD patients undergoing hemodialysis. RESULTS: Serum levels of total cholesterol, LDL cholesterol, and triglyceride exhibited drastic reduction, which completely disappeared 4 weeks after the final apheresis. Resting leg pain was improved in 6 cases even 4 weeks after final apheresis. Endothelium-dependent vasodilation was significantly increased 4 weeks after final apheresis (1.6 +/- 0.6 to 4.7 +/- 1.0%, p < 0.05). Levels of vascular growth factors, hepatocyte growth factor and vascular endothelial growth factor were not changed during treatment. CONCLUSIONS: These findings suggested that LDL apheresis is effective even in PAOD patients undergoing hemodialysis. Our findings suggest that its mechanisms of efficacy include improvement of vascular endothelial dysfunction, in addition to drastic but acute reduction of lipid levels. Since PAOD patients undergoing hemodialysis tend to be resistant to any treatment and are at high risk for lower-extremity amputation, LDL apheresis could be a useful strategy for treatment of them.

Renal and vascular protective effects of telmisartan in patients with essential hypertension.

It is known that the angiotensin receptor blockers (ARBs) have organ protective effects in patients with heart failure or renal impairment. Several studies have revealed that the ARB telmisartan has an organ protective effect, but there have been few studies directly comparing the effects of telmisartan and calcium antagonists, since most clinical studies on telmisartan have been conducted in treated patients or patients on combination therapy. The present study was conducted to compare the renal and vascular protective effects of telmisartan monotherapy and calcium antagonist monotherapy in untreated hypertensive patients. Forty-three patients with untreated essential hypertension were randomized to receive amlodipine (n=22) or telmisartan (n=21), which were respectively administered at doses of 5 mg and 40 mg once daily in the morning for 24 weeks. The patients were examined before and after treatment to assess changes of renal function, flow-mediated dilation (a parameter of vascular endothelial function), and brachial-ankle pulse wave velocity (baPWV; a parameter of arteriosclerosis). Before treatment, there were no significant differences in these parameters between groups. The decreases of urinary albumin excretion and baPWV, and the increase of flow-mediated dilation were significantly greater in the telmisartan group than the amlodipine group, while the antihypertensive effects were not significantly different between the two groups. In conclusion, these results suggest that telmisartan is more effective at protecting renal function and vascular endothelial function, and at improving arteriosclerosis than the calcium channel blocker in patients with essential hypertension.