Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney.

We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses.

Renal and vascular protective effects of ezetimibe in chronic kidney disease.

OBJECTIVE: Dyslipidemia is a risk factor for not only cardiovascular diseases (CVD), but also chronic kidney disease (CKD). Ezetimibe, a cholesterol absorption inhibitor, lowers cholesterol levels by inhibiting both extrinsic and intrinsic cholesterol absorption via the gastrointestinal duct. However, very few studies have examined its efficacy and safety for patients with dyslipidemia complicated with CKD. METHODS: Thirty-seven dyslipidemic patients (low density lipoprotein cholesterol (LDL-C) levels ≥120 mg/dL) complicated with CKD were given ezetimibe (10 mg/day) for twenty-four weeks. The efficacy and safety of the therapy, including the anti-atherosclerotic and renal protective effects, were then examined. RESULTS: Significant decreases were observed in the levels of LDL-C (158.9 ± 26.9 mg/dL→123.0 ± 31.8 mg/dL; p<0.0001), remnant-like lipoprotein cholesterol (9.3 ± 5.3 mg/dL→7.3 ± 3.8 mg/dL; p<0.05) and lipoprotein (a) (22.0 ± 16.1 mg/dL→16.4 ± 11.0 mg/dL; p<0.01). The estimated glomerular filtration rate did not change, but the urine protein to creatinine ratio decreased significantly (1,107.3 ± 1,454.2 mg/gCre→732.1 ± 1,237.8 mg/gCre; p<0.05). No changes were observed in the carotid intima media thickness, but the brachial-ankle pulse wave velocity decreased significantly (1,770.4 ± 590.3 cm/sec→1,702.5 ± 519.9 cm/sec; p<0.05). No adverse events were observed. CONCLUSION: Ezetimibe can be safely administered even to patients with CKD. The results of this study indicate that ezetimibe may provide some renal protection and suppress the complications of CVD in CKD patients.

Peritoneopericardial communication after aortic valve replacement in a peritoneal dialysis patient.

A 73-year-old male undergoing peritoneal dialysis (PD) for end-stage renal disease due to diabetic nephropathy was diagnosed with aortic stenosis and was admitted to our hospital in September, 2009. The patient underwent replacement of the ascending aorta with an artificial blood vessel plus aortic valve replacement without any notable complications. PD was restarted 3 days after the surgery and large amounts of light red fluid from the drain placed in the pericardium were observed just after resumption of PD solution. The patient was diagnosed with peritoneopericardial communication. PD was discontinued and hemodialysis was performed only with intermittent lavage of the peritoneal cavity. The amount of drainage was spontaneously decreased, and on the 17th day after surgery, PD was resumed. The patient is undergoing PD without recurrence of peritoneopericardial communication, 59 months after the onset of symptoms. Peritoneopericardial communication in a patient with PD developing after open-heart surgery is rare because such a case has been documented in only one case report. However, since massive pericardial effusion may cause severe cardiac problems, we consider that the communication between the peritoneal cavity and the pericardium needs to be checked for in patients with PD after cardiac surgery.

Olmesartan induces renoprotective effects by stimulating angiotensin type 2 receptors and reducing oxidative stress in diabetic nephropathy.

BACKGROUND: Angiotensin receptor blockers reduce the progression of diabetic nephropathy primarily by inhibiting angiotensin type 1 (AT(1)) receptors. In the present study, we investigated the role of angiotensin type 2 (AT(2)) receptors on the renoprotective effects of olmesartan in diabetic nephropathy. METHODS: Six-week-old mice were treated with streptozotocin and divided into four groups: the OLM group (mice treated with olmesartan), the OLM+Ang II group (mice treated with olmesartan and angiotensin II), the OLM+PD group (mice treated with olmesartan and the AT(2) antagonist PD 123319), and the vehicle group. Nondiabetic mice were used as controls. We measured blood glucose levels and urinary excretions of albumin and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is a marker for oxidative stress. RESULTS: Although urinary albumin excretion in the OLM and OLM+Ang II groups showed a tendency to be reduced compared to the vehicle group, it was significantly lower compared to the OLM+PD group. Urinary excretion of 8-OHdG was also significantly lower in the OLM and OLM+Ang II groups compared to the OLM+PD group. CONCLUSIONS: In diabetic nephropathy, the renoprotective effects of olmesartan are due not only to the blockade of AT(1) receptors, but also to a reduction in oxidative stress via stimulation of AT(2) receptors.

A Japanese case of proteinase 3 antineutrophil cytoplasmic autoantibody-associated pauci-immune-type crescentic glomerulonephritis without valvular endocarditis.

A 74-year-old male without recent medical treatment visited our hospital complaining of fever and lack of appetite. Upon examination severe azotemia, proteinuria, and urinary occult blood were noted, and the patient was admitted. Results of a blood test showed that his proteinase 3 antineutrophil cytoplasmic autoantibody (PR3-ANCA) level was high. A transthoracic echocardiogram indicated normal cardiac function and no valvular regurgitation or stenosis. Necrotizing glomerulonephritis accompanied by cellular crescentic bodies, but not granuloma, was noted on renal biopsy. An immunofluorescence study demonstrated no immunofluorescence staining in the glomerulus or in the tubulointerstitial or vascular compartments. No lesion was present in the lung or upper respiratory tract. The patient was diagnosed with PR3-ANCA-associated pauci-immune-type crescentic glomerulonephritis and treated with steroids. This treatment resulted in rapid normalization of C-reactive protein, and the PR3-ANCA level slowly decreased and converted to negative. The renal function, however, did not improve, and maintenance dialysis was introduced. No pulmonary or upper airway lesion has developed during 18 months of follow-up. PR3-ANCA-positive crescentic glomerulonephritis accompanied by valvular endocarditis has been described by several reports in Japan; however, this case was not complicated by valvular endocarditis. To our knowledge, this is the 4th case report describing PR3-ANCA-associated crescentic glomerulonephritis in Japan.

Decreased plasma level of vitamin C in chronic kidney disease: comparison between diabetic and non-diabetic patients.

BACKGROUND: A decreased plasma level of vitamin C has been reported to be associated with an increased risk of cardiovascular morbidity and mortality. Here, we sought to determine the vitamin C status of patients with chronic kidney disease and the pathophysiological role of vitamin C in these patients. METHODS: We studied 58 patients and evaluated the relationship between renal function and plasma vitamin C concentration, as well as the effect of diabetes on this relationship. Endothelium-dependent flow-mediated dilation of brachial artery was measured to assess the endothelial function. Serum malondialdehyde low-density lipoprotein was measured as a marker for oxidative stress. RESULTS: Plasma vitamin C concentration had a positive linear relationship with eGFR in both diabetic and non-diabetic patients (P = 0.006 and P = 0.004, respectively). When vitamin C concentration and eGFR relationships were compared in the two groups, vitamin C concentration was significantly lower in diabetic patients at every eGFR (P = 0.006). Flow-mediated vasodilatation of the brachial artery was positively correlated with vitamin C concentration in non-diabetic patients (P = 0.047) but not in diabetic patients. There was a negative correlation between serum malondialdehyde low-density lipoprotein and vitamin C concentration in non-diabetic patients (P = 0.044) but not in diabetic patients. CONCLUSIONS: Renal dysfunction was associated with a decrease in plasma vitamin C level. Moreover, decreased vitamin C may cause endothelial dysfunction via an increase in oxidative stress in non-diabetic chronic kidney disease patients.

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.

A patient with refractory nephrotic syndrome withdrawn from peritoneal dialysis.

A 67-year-old woman was admitted to our hospital because of anasarca due to refractory nephrotic syndrome and chronic renal insufficiency. Laboratory data indicated serum total protein of 4.8 g/dl, albumin of 1.5 g/dl, creatinine of 1.9 mg/dl and BUN of 17 mg/dl. Urinary protein excretion was 7.8 g/day. Because of severe atrophy of both kidneys, neither renal biopsy nor immunosuppressive treatment was performed. Since conservative management including bed rest, diet therapy, limitation of water intake and administration of diuretics was not effective, peritoneal dialysis therapy using icodextrin only at night was started. The amount of water removal was steadily secured without progressing renal dysfunction or decreasing urine volume. From day 290 onward, the urinary protein excretion was decreased to show complete remission and urine volume increased. On day 528, peritoneal dialysis was discontinued, and thereafter only peritoneal lavage was performed. On day 858, the catheter was removed from the abdominal cavity, and thereafter diuretics could be discontinued. The reason for the dramatic reduction of urinary protein in this patient is unclear. However, it is possible that the primary disease such as membranous nephritis showed remission while the patient was undergoing icodextrin peritoneal dialysis, which preserves renal function but not extracorporeal ultrafiltration or hemodialysis. Icodextrin peritoneal dialysis may be an alternative to hemodialysis for refractory fluid overload in patients with nephrotic syndrome and may have the advantage of preserving renal function.

Critical appraisal and pooled analysis of telmisartan alone or in combination with hydrochlorothiazide for achieving blood pressure goals.

Rigid control of blood pressure (BP) is essential to prevent cardiovascular disease. However, only about 40% of hypertensive patients undergoing pharmacological intervention with a single agent achieve their BP goals in contemporary clinical practice. Combined therapy using currently available agents is effective in maximizing treatment outcome, although it raises medical costs and decreases the drug compliance rate. To overcome such negative consequences, a combination tablet containing an angiotensin II receptor blocker (ARB) with a small dose of hydrochlorothiazide (HCTZ) is now available on the international market, including Japan. This article briefly describes the unique properties of telmisartan, a highly selective ARB for the angiotensin II type 1 receptor, including its long-acting characteristics and recent prospective multicenter randomized clinical trials, followed by a description of a newly-introduced combination tablet in Japan, which contains telmisartan and HCTZ. This article also reviews its safety and efficacy based on currently available evidence. Finally, evidence comparing telmisartan/HCTZ with other combination therapies is presented.

Efficacy of an L- and N-type calcium channel blocker in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla.

The rostral ventrolateral medulla is an important regulation center of sympathetic nerve activity. Several clinical studies have indicated a possible association between essential hypertension and neurovascular compression of the rostral ventrolateral medulla. We have found that patients with essential hypertension and neurovascular compression of the rostral ventrolateral medulla by adjacent arteries have increased sympathetic nerve activity and that microvascular decompression of the rostral ventrolateral medulla normalizes blood pressure and sympathetic nerve activity. Although sympatholytic agents are expected to lower blood pressure in these patients, this remains to be clarified. In this study, we evaluated the effect of cilnidipine, a calcium channel blocker that blocks both vascular L-type and sympathetic N-type Ca(2+) channels in hypertensive patients with neurovascular compression. Using high-resolution magnetic resonance imaging, 46 patients with untreated essential hypertension were distributed into those with and without neurovascular compression of the rostral ventrolateral medulla. All patients were prescribed 10 mg of cilnidipine for 16 weeks. Office and home blood pressure, plasma norepinephrine and left ventricular mass index were measured by echocardiography before and after cilnidipine treatment, and changes were compared between the two groups. At baseline, plasma norepinephrine was significantly higher in patients with neurovascular compression. Decreases in office and home blood pressure, plasma norepinephrine and left ventricular mass index were significantly greater in patients with neurovascular compression. These results suggest that cilnidipine lowers blood pressure by inhibiting enhanced sympathetic nerve activity and reduces left ventricular mass in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla.

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.