Addition of aliskiren to olmesartan ameliorates tubular injury in chronic kidney disease patients partly by reducing proteinuria.

INTRODUCTION: Tubular injury is more important than glomerulopathy for renal prognosis in chronic kidney disease (CKD) patients. Numerous studies have demonstrated the active participation of the renin-angiotensin system (RAS) in CKD. However, whether addition of aliskiren, a direct renin inhibitor, to olmesartan improves renal tubular injury in CKD patients is unknown. METHODS: This study compared the effects of aliskiren (300 mg daily), olmesartan (40 mg daily), and its combination therapy on urinary L-fatty acid binding protein (L-FABP), a marker of tubular injury in stage I or II CKD patients. It also examined which clinical variables were independently correlated with tubular damage. RESULTS: Olmesartan or aliskiren monotherapy for 6 months comparably decreased blood pressure (BP) and proteinuria. BP and proteinuria levels were reduced more by combination therapy than by either monotherapy. Olmesartan or aliskiren decreased urinary L-FABP level, and combination therapy produced more incremental reduction in L-FABP level relative to each monotherapy. Multiple stepwise regression analysis revealed that BMI, low-density lipoprotein (LDL)-cholesterol and proteinuria were independently related to urinary L-FABP level. CONCLUSIONS: The present study demonstrated that addition of aliskiren to olmesartan decreased urinary L-FABP level partly via reduction of proteinuria in stage I or II CKD patients.

Changes in urinary albumin excretion, inflammatory and oxidative stress markers in ADPKD patients with hypertension.

BACKGROUNDS: Autosomal dominant polycystic kidney disease (ADPKD) progresses more quickly to end-stage renal disease in patients with hypertension than in their normotensive counterparts. The authors investigated the effect of telmisartan versus enalapril on systolic and diastolic blood pressure (SBP and DBP), urinary albumin excretion (UAE), serum high mobility group box-1 protein (HMGB1), serum interleukin (IL)-6 and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in patients with hypertensive ADPKD. METHODS: Twenty patients with hypertensive ADPKD with good renal function were randomly assigned to 1 of 2 treatments: telmisartan 80 mg once daily (n = 10) or enalapril 10 mg once daily (n = 10). Treatment lasted 12 months. SBP, DBP, serum creatinine, UAE, HMGB1, IL-6 and urinary 8-OHdG levels were measured before and 6 and 12 months after treatment. RESULTS: Both SBP and DBP were significantly reduced after treatment (P < 0.001) in both groups. Serum creatinine changed little during the experimental period in either group. UAE, serum HMGB1, serum IL-6 and urinary 8-OHdG levels were significantly decreased after treatment (UAE, HMGB1 and IL-6, P < 0.001; and 8-OHdG, P < 0.01 versus baseline levels) in both groups. However, the decreases in UAE, serum HMGB1 and serum IL-6 were significantly greater in the telmisartan group than in the enalapril group at 6 months (P < 0.05, P < 0.01 and P < 0.01, respectively) and 12 months (all, P < 0.05). CONCLUSIONS: Telmisartan seems to be equivalent to enalapril in lowering BP, but telmisartan has more potent renoprotective, anti-inflammatory and antioxidative effects than enalapril in patients with hypertensive ADPKD.

Renovascular protective effects of erythropoietin in patients with chronic kidney disease.

BACKGROUND/AIMS: Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia. METHODS: The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP--a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG--a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers. RESULTS: After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period. CONCLUSION: These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

Polymyxin B-immobilized fiber hemoperfusion in a high school football player with septic shock caused by osteitis pubis.

A 17-year-old male high school football player treated by polymyxin B-immobilized fiber (PMX-F) hemoperfusion for mild-moderate septic shock caused by osteitis pubis is described in this study. He was admitted for inguinal pain, gait disturbance, and high fever (40.6°C). His white blood cell (WBC) count and C-reactive protein (CRP), endotoxin, and procalcitonin (PCT) levels were significantly elevated. His blood pressure was 76/46 mm Hg. Magnetic resonance imaging showed bone and muscle injury at the pubic symphysis. Septic shock with high blood endotoxin and PCT concentrations was diagnosed, and the patient was treated with antibiotics, γ-globulin, and dopamine on the admission day. However, the septic shock did not improve. On day 3, we performed direct hemoperfusion twice using a PMX-F column. After the second PMX-F treatment, the patient's temperature decreased to 37.0°C, and his WBC count, CRP levels, blood endotoxin, and PCT levels decreased. The inguinal pain diminished, and the patient's blood pressure increased to 112/76 mm Hg. He was discharged on day 10 after admission. This case reflects association of PMX-F with decreased endotoxin, PCT, and CRP, suggesting the association of PMX-F with clinical improvement in mild-moderate sepsis in a young athlete.

Hemoperfusion treatment in a septic shock patient with autosomal dominant polycystic kidney disease and increased HMGB1 protein levels.

This case report describes polymyxin B-immobilized fiber (PMX-F) treatment of septic shock caused by pyelonephritis in a 68-year-old woman with autosomal dominant polycystic kidney disease. She was admitted for severe lower left abdominal pain, high fever (40°C) and gross hematuria. Her endotoxin and high-mobility group box-1 protein (HMGB1) levels were extremely elevated. Her blood pressure was 68/36 mm Hg. Urinalysis revealed innumerable white blood cells (WBCs). Blood and urine cultures were positive for Klebsiella pneumoniae and Pseudomonas aeruginosa. Plain abdominal radiography showed large kidney shadows and calcium deposition. Septic shock with endotoxemia was diagnosed. Her symptoms of septic shock persisted for 3 days with antibiotics, γ-globulin and dopamine. Direct hemoperfusion was performed twice with a PMX-F column. The patient's body temperature, WBC count and C-reactive protein level decreased. Her blood endotoxin level and blood HMGB1 level also decreased to an almost normal level. She was discharged on day 23 after admission.

Calcium channel blocker inhibition of AGE and RAGE axis limits renal injury in nondiabetic patients with stage I or II chronic kidney disease.

BACKGROUND: There is a growing body of evidence that advanced glycation end products (AGE) and their receptor (RAGE) system are implicated in chronic kidney disease (CKD). We have previously found that a long-acting calcium channel blocker, azelnidipine, but not amlodipine, improves renal injury in CKD patients. However, little is known about the effect of azelnidipine on the AGE-RAGE axis in humans. In this study, we examined whether azelnidipine addition could have renoprotective properties in hypertensive CKD patients by reducing serum levels of AGE and soluble form of RAGE (sRAGE). Thirty nondiabetic stage I or II CKD patients who had already been treated with angiotensin II receptor blockers were enrolled in this study. HYPOTHESIS: We hypothesized that azelnidipine treatment could limit renal injury partly by blocking the AGE-RAGE axis. METHODS: Patients were randomly divided into 2 groups; one group was treated with 16 mg azelnidipine and the other with 5 mg amlodipine once daily. They were followed up for 6 months. RESULTS: Proteinuria was positively correlated with circulating AGE and sRAGE levels in our subjects. Both drugs exhibited comparable and significant blood pressure (BP)-lowering effects. Although neither of them affected glucose, glycated hemoglobin, lipid levels, and estimated glomerular filtration rate, treatment with azelnidipine, but not amlodipine, decreased circulating AGE, sRAGE, proteinuria, and urinary levels of liver-type fatty acid binding protein, a marker of tubular injury, in a BP-lowering-independent manner. CONCLUSIONS: Our present results suggest that azelnidipine may exert renoprotective properties in nondiabetic hypertensive CKD patients via its unique inhibitory effects on the AGE-RAGE axis.

Suppression of high-mobility group box-1 and receptor for advanced glycation end-product axis by polymyxin B-immobilized fiber hemoperfusion in septic shock patients.

PURPOSE: Endotoxin plays a role in organ failure in septic shock patients. High-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) axis is also involved in septic shock. We investigated here the effects of endotoxin removal by polymyxin B-immobilized polystyrene fiber (PMX-F) treatment on circulating levels of HMGB1, soluble RAGE (sRAGE), and interleukin-6 (IL-6) in septic shock patients. MATERIALS AND METHODS: Fifteen septic shock patients (70.1 ± 8.5 years) and 15 age- and sex-matched healthy volunteers were included in this study. Polymyxin B-immobilized polystyrene fiber treatment was repeated twice, separated by an interval of 24 hours. Blood samples were collected before and immediately after the second PMX-F treatment for determinations of biochemical variables. RESULTS: Systolic and diastolic blood pressures were significantly lower, and endotoxin, IL-6, HMGB1, and sRAGE levels were higher in septic shock patients compared with healthy volunteers. These parameters were significantly improved by PMX-F treatment. The changes in endotoxin obtained by PMX-F treatment were correlated with those in HMGB1, sRAGE, and IL-6. Multiple stepwise regression analysis revealed that IL-6 was a sole independent correlate of endotoxin. CONCLUSIONS: Our present study suggests that PMX-F treatment could block the HMGB1-RAGE axis in patients with septic shock via removal of endotoxin-induced inflammatory reactions.

Increased levels of soluble receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) are associated with death in patients with acute respiratory distress syndrome.

OBJECTIVES: Receptor for advanced glycation end products (RAGE) plays a role in inflammatory reactions. Soluble RAGE (sRAGE) level is elevated in patients with acute respiratory distress syndrome (ARDS). However, which clinical parameters and inflammatory biomarkers including sRAGE are associated with death in ARDS patients remain unknown. DESIGN AND METHODS: We examined whether sRAGE level was independently associated with death in 20 ARDS patients with severe infection. RESULTS: Compared with age- and sex-matched control subjects, blood pressure levels were lower and KL-6, high mobility group box 1 (HMGB1), interleukin-6 and sRAGE levels were higher in ARDS patients. In multivariate analysis, sRAGE was associated with death in ARDS patients, but severity of illness was not. HMGB1 was a sole independent correlate of sRAGE. CONCLUSIONS: This study demonstrated that sRAGE was independently associated with death in ARDS patients. Our present results suggest active involvement of HMGB1-RAGE axis in poor prognosis of ARDS.

Oral adsorbent AST-120 ameliorates tubular injury in chronic renal failure patients by reducing proteinuria and oxidative stress generation.

AST-120 is an oral adsorbent that attenuates the progression of chronic renal failure (CRF) and improves the prognosis of the patients under dialysis. Although tubulointerstitial injury is more important than glomerulopathy in terms of renal prognosis in patients with CRF, effect of AST-120 on tubular injury in CRF patients remains unknown. In this study, we examined whether and how AST-120 treatment could improve tubular damage in nondiabetic CRF patients. Fifty nondiabetic CRF patients were enrolled in the present study and divided into 2 groups: one was the AST-120-treated group (15 men and 10 women) and the other was the age-, sex-, and clinical variables-matched non-AST-120-treated control group. Patients were followed up for 12 months. We investigated the effects of AST-120 on serum levels of interleukin-6 (IL-6), proteinuria, and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and L-fatty acid binding protein (L-FABP), markers of oxidative stress and tubular injury, respectively. AST-120 treatment (6 g/d), but not control treatment, for 12 months significantly reduced IL-6, proteinuria, and urinary excretion levels of L-FABP and 8-OHdG, and inhibited the increase in serum creatinine in CRF patients. In univariate analyses, L-FABP levels were correlated with age, proteinuria, 8-OHdG, and IL-6. In multiple stepwise regression analysis, proteinuria and urinary 8-OHdG levels were independently related to L-FABP levels (R² = 0.605). Our present study demonstrated for the first time that AST-120 improved tubular injury in nondiabetic CRF patients. AST-120 may exert beneficial effects in CRF patients by protecting tubular damage partly via reduction of proteinuria and oxidative stress generation.

Atorvastatin reduces proteinuria in non-diabetic chronic kidney disease patients partly via lowering serum levels of advanced glycation end products (AGEs).

There is accumulating evidence that advanced glycation end products (AGEs) play a role in the development and progression of chronic kidney disease (CKD). We have previously found that atorvastatin treatment significantly reduces serum levels of AGEs in type 2 diabetic patients and subjects with non-alcoholic steatohepatitis in a cholesterol lowering-independent manner. In this study, we examined whether atorvastatin could reduce proteinuria partly via reduction of serum levels of AGEs in non-diabetic CKD patients. Ten non-diabetic normotensive stage I or II CKD patients with dyslipidemia were enrolled. Patients were treated with atorvastatin (10 mg/day) for 1 year. All subjects underwent determination of blood chemistries, proteinuria and serum levels of AGEs at baseline and after 1 year. Atorvastatin treatment for 1 year significantly decreased circulating levels of total cholesterol, LDL-cholesterol, triglycerides, and AGEs, while it increased HDL-cholesterol levels. Further, although atorvastatin treatment did not affect estimated glomerular filtration rate, it significantly reduced proteinuria. In univariate analyses, proteinuria levels were correlated with total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol (inversely) and AGEs. Multiple stepwise regression analysis revealed that AGE level was a sole independent correlate of proteinuria. In this initial examination of the patients in this study, our present study suggests that atorvastatin could decrease proteinuria in non-diabetic CKD patients with dyslipidemia partly via reduction of serum levels of AGEs. Atorvastatin may have AGE-lowering effects in CKD patients as well that could contribute to renoprotective properties of this agent.

Effects of telmisartan and enalapril on renoprotection in patients with mild to moderate chronic kidney disease.

BACKGROUND: Blocking the renin-angiotensin system (RAS) with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors protects against renal injury in patients with chronic kidney disease (CKD). The aim of this study was to compare the chronic effects of telmisartan and enalapril on proteinuria, urinary liver-type fatty acid-binding protein (L-FABP) and endothelin (ET)-1 levels in patients with mild CKD. MATERIALS AND METHODS: Thirty CKD patients with mild to moderate renal insufficiency (20 men and 10 women; mean age, 37 years; estimated glomerular filtration rate (eGFR) > 60 mL min(-1) and blood pressure > 130/85 mmHg) were included in the study. Patients were randomly assigned to receive telmisartan at 80 mg day(-1) (n = 15) or enalapril at 10 mg day(-1) (n = 15). We measured blood pressure, serum creatinine, eGFR, urinary protein, L-FABP and ET-1 before the start of treatment and 6 and 12 months after the start of treatment. RESULTS: The blood pressure reduction rate was similar between the two groups. Urinary protein, L-FABP and ET-1 levels were significantly reduced in both groups 6 and 12 months (P < 0.001) after treatment, but the reduction rates were more pronounced in patients receiving telmisartan than in those receiving enalapril (P < 0.001). Estimated glomerular filtration rate was increased similarly in both groups at 12 months. CONCLUSIONS: The study results suggest that telmisartan results in a greater reduction of urinary markers than does enalapril and that this effect occurs by a mechanism independent of blood pressure reduction. It would be needed to investigate whether the differences may be distinct or not the same when other dosages are used.

Comparative effects of benidipine and amlodipine on proteinuria, urinary 8-OHdG, urinary L-FABP, and inflammatory and atherosclerosis markers in early-stage chronic kidney disease.

INTRODUCTION: We examined the effects of 2 calcium channel blockers, benidipine (T-, L-, and N-type) and amlodipine (L- and N-type), on renal, inflammatory, oxidative, and atherosclerosis markers in hypertensive patients with mild chronic kidney disease (CKD). METHODS: Forty hypertensive patients with CKD were assigned randomly to either of the 2 treatments: 8 mg benidipine once daily (n = 20, group A) or 5 mg amlodipine once daily (n = 20, group B). Treatment was continued for 12 months. Blood pressure, serum creatinine, estimated glomerular filtration rate, urinary protein excretion, urinary liver-type fatty acid-binding protein, interleukin-6, high mobility group box-1 protein, urinary 8-hydroxy-2'-deoxyguanosine, pulse wave velocity, intima-media thickness, and blood asymmetric dimethylarginine were monitored. RESULTS: Blood pressure decreased equally in both groups (P < 0.001, at 6 and 12 months versus before treatment). Serum creatinine and estimated glomerular filtration rate changed little during the experimental period in each group. However, urinary protein excretion (P < 0.001), urinary liver-type fatty acid-binding protein (P < 0.001), urinary 8-hydroxy-2'-deoxyguanosine (P < 0.001), blood interleukin-6 (P < 0.001), blood high mobility group box-1 (P < 0.05), and pulse wave velocity (P < 0.01) decreased more in group A than in group B with 12 months of treatment. The percent reductions in intima-media thickness and blood asymmetric dimethylarginine were significantly greater in group A than in group B (P < 0.001). CONCLUSIONS: Benidipine is more effective than amlodipine for protecting renal function and potentially for ameliorating atherosclerosis in hypertensive patients with mild CKD. T-type calcium channel blockers may be effective in patients with CKD.

Co-administration of ezetimibe enhances proteinuria-lowering effects of pitavastatin in chronic kidney disease patients partly via a cholesterol-independent manner.

Since co-administration of ezetimibe, a specific inhibitor of cholesterol absorption into the intestine, has been shown to augment lipid-lowering effects of statins, ezetimibe plus statins is a novel therapeutic strategy for the treatment of dyslipidemia in high-risk patients. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease (CKD). However, effects of co-administration of ezetimibe with statins on renal damage and dysfunction in CKD patients remain unknown. In this study, we examined whether co-administration of ezetimibe with pitavastatin could augment renoprotective properties of pitavastatin in non-diabetic CKD patients with dyslipidemia. Total cholesterol, LDL-cholesterol and triglycerides levels were reduced more by co-administration of ezetimibe (10mg/day) with pitavastatin (2mg/day) (n=10) than by pitavastatin alone (n=10). In addition, ezetimibe plus pitavastatin treatment produced significant incremental reduction in proteinuria related to pitavastatin therapy alone. In univariate analyses, proteinuria was correlated with plasma levels of total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol (inversely), asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and urinary excretion levels of L-fatty acid binding protein (L-FABP), a marker of tubular injury and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker. Multiple stepwise regression analysis revealed that LDL-cholesterol (p<0.001) and urinary excretion levels of L-FABP (p=0.001) and 8-OHdG (p<0.001) were independently related to proteinuria (R(2)=0.969). Our present study demonstrated for the first time that co-administration of ezetimibe enhanced proteinuria-lowering effects of pitavastatin in non-diabetic CKD patients partly via a cholesterol-independent manner. Ezetimibe may have pleiotropic actions that could contribute to renoprotective properties of this lipid-lowering agent.

Positive association of serum levels of advanced glycation end products and high mobility group box-1 with asymmetric dimethylarginine in nondiabetic chronic kidney disease patients.

There is accumulating evidence that engagement of the receptor for advanced glycation end products (RAGE) with ligands such as advanced glycation end products (AGEs) and high mobility group box-1 (HMGB-1) elicits vascular inflammation, thus contributing to the increased risk for cardiovascular disease. Furthermore, enhanced accumulation of asymmetric dimethylarginine (ADMA) plays a role in cardiovascular disease in chronic kidney disease (CKD) patients. However, the relationships among serum levels of AGEs, HMGB-1, soluble form of RAGE (sRAGE), and ADMA are largely unknown. The aim of the present study is to determine their relationships in CKD patients. Twenty nondiabetic normotensive CKD patients with dyslipidemia and 20 age- and sex-matched healthy controls were enrolled. All subjects underwent determination of blood chemistries; urinary proteinuria; and serum levels of AGEs, HMGB-1, sRAGE, and ADMA. Serum AGE, HMGB-1, sRAGE, and ADMA levels in CKD patients were significantly higher than those in control subjects. Circulating levels of AGEs in CKD patients were positively associated with sRAGE and ADMA, and HMGB-1 with ADMA, but not sRAGE. There were no significant associations among these markers and serum creatinine, estimated glomerular filtration rate, proteinuria, and lipid levels. In multiple regression analyses, AGEs and HMGB-1 were independently correlated with ADMA. The present study demonstrated that AGE and sRAGE levels were correlated with each other and that AGEs and HMGB-1 were independently associated with ADMA in nondiabetic CKD patients. Elevation of the RAGE ligands may enhance ADMA levels, suggesting the active involvement of AGE/HMGB-1-RAGE-ADMA axis in CKD patients.

Effect of polymyxin B-immobilized fiber hemoperfusion on serum high mobility group box-1 protein levels and oxidative stress in patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is characterized by diffuse inflammation in the lung and resultant permeability edema. Polymyxin B-immobilized fiber (PMX-F) hemoperfusion is effective for sepsis-induced ARDS. High mobility group box-1 protein (HMGB1) is newly recognized as a proinflammatory cytokine. The aim of the study was to determine whether blood HMGB1 levels are increased in patients with ARDS and whether PMX-F treatment affects these levels. Subjects were 20 sepsis-induced patients with ARDS treated by PMX-F column and 20 age-matched healthy volunteers. Polymyxin B-immobilized fiber treatment was carried out twice at a rate of 100 ml/min for 2 hours. Systolic and diastolic blood pressures, the PaO2/FiO2 (PF) ratio and endotoxin, HMGB1, and urinary 8-hydroxy-2'-deoxyguanosine (OHdG) levels were measured before and after PMX-F treatment. Blood endotoxin levels, blood HMGB1 levels, and urinary 8-OHdG levels were significantly higher in patients with ARDS than in healthy volunteers. Systolic and diastolic blood pressures and the PF ratio increased significantly after PMX-F treatments. Polymyxin B-immobilized fiber treatment reduced blood endotoxin, blood HMGB1, and urinary 8-OHdG levels significantly. These data suggest that HMGB1 and oxidative stress play a role in the pathogenesis of ARDS and that PMX-F treatment may ameliorate increased blood HMGB1 and urinary 8-OHdG levels in patients with ARDS.

Ezetimibe decreases serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner.

Synthesis of nitric oxide (NO) can be blocked by inhibition of nitric oxide synthase (NOS) active site with guanidino-substituted analogues of l-arginine such as asymmetric dimethylarginine (ADMA). There is growing evidence that elevation of serum ADMA levels play a role in the progression of atherosclerosis and chronic kidney disease (CKD) in high-risk patients. Further, dyslipidemia contributes to cardiorenal disease as well. However, effects of ezetimibe, a specific inhibitor of cholesterol absorption and widely used drug for the treatment of dyslipidemia, on serum ADMA levels and renal injury remain unknown. In this study, we examined whether ezetimibe treatment decreased serum levels of ADMA, proteinuria and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and l-fatty acid binding protein (l-FABP), markers of oxidative stress and tubular injury, respectively and investigated their relationships in 10 non-diabetic CKD patients with dyslipidemia. Ezetimibe treatment (10mg/day) for 6 months significantly decreased circulating levels of LDL-cholesterol, triglycerides and ADMA, while it increased HDL-cholesterol levels. Further, ezetimibe treatment significantly reduced urinary excretion levels of protein, l-FABP and 8-OHdG. In univariate analyses, serum ADMA levels were correlated with urinary protein, l-FABP and 8-OHdG levels. In multiple stepwise regression analysis, proteinuria was independently correlated with ADMA. Our present study demonstrated for the first time that ezetimibe decreased serum ADMA levels and improved renal injury in non-diabetic CKD patients with dyslipidemia in a cholesterol-independent manner. Ezetimibe may have pleiotropic actions, that is, ADMA-lowering and anti-oxidative effects, that could contribute to renoprotective properties of this lipid-lowering agent.

Circulating levels of advanced glycation end products (AGE) and interleukin-6 (IL-6) are independent determinants of serum asymmetric dimethylarginine (ADMA) levels in patients with septic shock.

There is a growing body of evidence that nitric oxide (NO) excess plays a central role in the pathogenesis of hypotension and organ failure in patients with septic shock. In addition, recently, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, has been shown to contribute to the regulation of vascular tone via modulation of NO generation in vivo. However, the kinetics and regulation of serum levels of ADMA in patients with septic shock are largely unknown. Since high mobility group box 1 (HMGB1)-receptor for advanced end products (RAGE) axis is supposed to be involved in the lethality in septic shock, we examined the correlations among serum levels of ADMA, endotoxin, interleukin-6 (IL-6), soluble form of RAGE (sRAGE) and RAGE ligands such as HMGB1 and advanced glycation end products (AGE) in septic shock patients. Fifteen septic shock patients (10 males and 15 females, mean age: 70.1+/-8.5 years) and fifteen age- and sex-matched healthy volunteers were included in this study. The criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference were used for diagnosis of septic shock. All the subjects underwent a complete history and physical examination, determination of blood chemistries, including serum levels of ADMA, endotoxin, IL-6, HMGB1, AGE and sRAGE. Linear and multiple stepwise regression analysis were performed for the determinants of serum levels of ADMA. Serum levels of ADMA were significantly higher than those in healthy volunteers (0.98+/-0.21nmol/mL vs. 0.30+/-0.05nmol/mL, p<0.0001). In univariate analysis, creatinine (p<0.005), endotoxin (p<0.001), IL-6 (p<0.001), HMGB1 (p<0.001), AGE (p<0.001) and sRAGE (p<0.001) were significantly associated with serum ADMA levels. After performing multivariate stepwise regression analyses, IL-6 (p=0.001), AGE (p=0.002) and creatinine (p=0.013) still remained significant independently. The present study is the first demonstration that ADMA levels were significantly elevated in patients with septic shock and that serum IL-6, AGE and creatinine levels were independent determinants of ADMA in these patients. Given the harmful effects of NO excess in septic shock, ADMA levels may be increased as a counter-system against inflammation and oxidative stress in this life-threatening disorder.

Renoprotective effect of telmisartan in patients with chronic kidney disease.

Although the activation of the renin-angiotensin system has a major role in the development of chronic renal failure, little is known about the effect of angiotensin receptor blockers on tubulointerstitial injury. To evaluate the renoprotective effect of telmisartan, we measured urinary protein excretion, urinary liver-type fatty acid binding protein (L-FABP) excretion, and urinary collagen IV in 30 hypertensive patients with chronic kidney disease (CKD). These patients were randomly assigned to receive 40 mg/day (n = 15) or 80 mg/day (n = 15) of telmisartan before the initiation of treatment and 6 and 12 months after treatment. Both doses of telmisartan reduced systolic and diastolic blood pressure after 6 (p < 0.001) and 12 (p < 0.001) months compared with baseline levels. Blood pressure reduction rate were similar between both doses. Urinary protein, urinary L-FABP excretion, and urinary collagen IV levels declined significantly 6 (p < 0.001) and 12 (p < 0.001) months after telmisartan treatment in both doses. The reduction rate in parameters was more pronounced in patients receiving 80 mg/day compared with those taking 40 mg/day telmisartan at 12 months (p < 0.001). Telmisartan reduces proteinuria, urinary L-FABP excretion, and urinary collagen IV levels in hypertensive CKD patients.

Comparison of renal and vascular protective effects between telmisartan and amlodipine in hypertensive patients with chronic kidney disease with mild renal insufficiency.

The present study was conducted to compare the renal and vascular protective effects of telmisartan and amlodipine in untreated hypertensive chronic kidney disease (CKD) patients with moderate renal insufficiency. Thirty hypertensive CKD patients were randomly assigned to receive telmisartan 40 mg (n = 15) or amlodipine 5 mg (n = 15) once daily for 12 months. Changes in blood pressure, serum creatinine, 24-h creatinine clearance (Ccr), proteinuria, brachial-ankle pulse wave velocity (baPWV), intima-media thickness (IMT), plasma interleukin-6 (IL-6), plasma matrix metalloproteinase (MMP)-9 and lipid profiles were monitored in all patients. Before treatment, there were no significant differences in these parameters between the telmisartan and amlodipine groups. Over the 12 month observation period, blood pressure decreased equally in both groups. However, serum creatinine, proteinuria, baPWV, IMT, plasma levels of IL-6 and MMP-9 and total cholesterol decreased and 24-h Ccr increased more strikingly in the telmisartan group than the amlodipine group. These data suggest that telmisartan is more effective than amlodipine for protecting renovascular functions, and potentially for ameliorating atherosclerosis, in hypertensive CKD patients with moderate renal insufficiency.