Chifuyu Ushiyama

Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients.

Urinary endothelin (ET)-1 excretion is present in non-insulin dependent diabetes (NIDDM) patients with microalbuminuria, and an increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. The aim of the present study was to determine whether various drugs alter urinary ET-1 levels and urinary albumin excretion (UAE) in NIDDM patients with microalbuminuria. Forty-five NIDDM patients with microalbuminuria were randomly assigned to three groups: those treated with pioglitazone at 30 mg/day (n=15), those treated with glibenclamide at 5 mg/day (n=15), and those treated with voglibose at 0.6 mg/day (n=15). Patients received these drugs for 3 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in these patients before and after treatment. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little among the three groups. UAE in the 45 NIDDM patients (156.2+/-42.8 microg/min) was greater than that in 30 healthy controls (8.2+/-2.6 microg/min) (P<.001). Urinary ET-1 levels in the NIDDM patients (8.7+/-1.3 ng/g urinary creatinine (UC)) were significantly higher than that in the controls (2.4+/-0.2 ng/g UC) (P<.01). Plasma ET-1 levels, however, in the NIDDM patients (1.3+/-0.4 pg/ml) did not differ significantly from the levels in healthy controls (1.0+/-0.6 pg/ml). Pioglitazone but no glibenclamide or voglibose reduced UAE from 142.8+/-42.2 to 48. 4+/-18.2 microg/min (P<.01) and urinary ET-1 levels from 8.6+/-1.3 to 3.4+/-0.5 ng/g UC (P<.01). These data suggest pioglitazone to be effective in reducing UAE and urinary ET-1 concentrations in NIDDM patients with microalbuminuria.

Effect of Cerivastatin on Urinary Albumin Excretion and Plasma Endothelin-1 Concentrations in Type 2 Diabetes Patients with Microalbuminuria and Dyslipidemia

Background/Aims: To determine whether cerivastatin, a newly developed novel synthetic potent statin, exerts a renoprotective effect, we assessed urinary albumin excretion (UAE) and plasma and urinary endothelin (ET)-1 concentrations in normotensive microalbuminuric type 2 diabetes patients with dyslipidemia. Methods: Sixty normotensive type 2 diabetic patients (38 men and 22 women; mean age 56.5 years) with microalbuminuria (20–200 µg/min) and dyslipidemia (total cholesterol >200 mg/dl, LDL cholesterol >160 mg/dl, HDL cholesterol <35 mg/dl, and triglyceride >150 mg/dl) were enrolled in a double-blind study for 6 months, receiving either cerivastatin (0.15 mg/day) or placebo. Plasma and urinary ET-1 concentrations were measured by radioimmunoassay. Results: Cerivastatin did not affect serum creatinine and HbA1c levels, and reduced systolic blood pressure slightly, but not significantly. Plasma levels of total cholesterol and LDL cholesterol were significantly reduced (p < 0.01), and plasma triglyceride levels were also reduced significantly (p < 0.05) after 6 months of cerivastatin treatment. A concomitant significant decrease in UAE (p < 0.01), and urinary and plasma ET-1 concentrations (p < 0.01) were found during this period. Conclusion: The use of cerivastatin is associated with decreased microalbuminuria and plasma and urinary ET-1 levels in microalbuminuric patients with type 2 diabetic mellitus and speculate that this may represent an amelioration of renal injury.

Urinary Podocytes for the Assessment of Disease Activity in Lupus Nephritis

BackgroundDetection of podocytes in the urine indicates that severe injury of podocytes occurred in the glomerulus in children. MethodsThe pathological significance of podocytes in the urine was determined in patients with lupus nephritis. Podocytes were detected by immunofluorescence using a monoclonal antibody against podocalyxin present on the surface of podocytes. Subjects who participated in the present study were of the following types: patients with systemic lupus erythematosus with stable renal function (group A, n = 8; WHO classes IIIa, b, IVb, and IVc at the time of biopsy); patients with clinically active lupus nephritis (group B, n = 8; WHO classes IVb and IVc); and healthy control subjects (group C, n = 10). ResultsPodocytes were absent in the urine of subjects in groups A and C. However, podocytes were present in the urine of group B subjects. Patients in group B were examined monthly for urinary podocytes and were treated with methylprednisolone followed by prednisolone. Urinary podocytes were absent in all patients in group B after treatment. ConclusionsThese data indicate that urinary podocytes may be markers of the severity of lupus nephritis and that steroid therapy may be effective for podocyte injury in lupus nephritis.

The urinary podocyte as a marker for the differential diagnosis of idiopathic focal glomerulosclerosis and minimal-change nephrotic syndrome.

Background/Aims: Detection of podocytes in the urine sediment of children indicates that severe podocyte injury occurred in the glomerulus. Focal glomerulosclerosis (FGS) and minimal-change nephrotic syndrome (MCNS) are kidney diseases characterized by massive proteinuria. The aim of the present study was to determine whether urinary podocytes can be detected in patients with idiopathic FGS or MCNS and whether immunosuppression therapy alters these cells. Methods: Twenty patients with MCNS (nephrotic stage, n = 12; remission stage, n = 8), 15 patients with FGS and 20 healthy controls were included in the present study. Urinary podocytes were stained by immunofluorescence. All patients with MCNS at the nephrotic stage received prednisolone for 6 months, and all patients with FGS received some form of immunosuppression therapy including prednisolone, cyclophosphamide or mizoribine for 12 months. Results: The 12 nephrotic-stage MCNS patients achieved remission after treatment. Seven of the 15 FGS patients also achieved remission, but the other 8 remained in the nephrotic stage. Urinary podocytes were not detected in any patient with MCNS nor were they detected in healthy controls. Urinary podocytes were detected in all FGS patients (mean, 4.2 cells/ml) before treatment and the number of cells decreased in the 7 patients who achieved remission. The number of podocytes was unchanged in the other 8 patients even after treatment. Conclusion: Urinary podocytes may be a useful diagnostic indicator for differentiation between FGS and MCNS. These cells may also mark disease progression in cases of FGS.

Treatment with polymyxin B-immobilized fiber reduces platelet activation in septic shock patients: Decrease in plasma levels of soluble P-selectin, platelet factor 4 and β-thromboglobulin

Objective: To clarify whether plasma concentrations of soluble P-selectin, platelet factor-4 (PF-4) and β-thromboglobulin (βTG) are altered in patients with septic shock and whether polymyxin B-immobilized fiber (PMX-F) treatment affects these changes.¶Subjects: Thirty patients with septic shock who were treated with PMX-F (group A), 20 such patients who received conventional therapies (group B) and 20 healthy control subjects (group C).¶Methods: ELISA using commercial kits. Endotoxin elimination by direct hemoperfusion using PMX-F.¶Results: Blood endotoxin levels decreased significantly from 49.4 ± 8.8 pg/ml to 13.0 ± 4.5 pg/ml after PMX-F treatment. The pretreatment plasma concentrations of soluble P-selectin, PF-4 and βTG in patients in groups A and B were significantly higher than those in group C (p < 0.001). Plasma concentrations of these factors decreased significantly in group A after PMX-F treatment (p < 0.01); however, the concentrations in group B were not altered after conventional treatment. The survival rate of group A (60%) was higher than that of group B (30%).¶Conclusions: Our findings suggest that soluble P-selectin, PF-4 and βTG may be associated with septic shock and that PMX-F is effective in reducing these markers in patients with septic shock.

Elevation of Serum Levels of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-1 and Type IV Collagen, and Plasma Levels of Metalloproteinase-9 in Polycystic Kidney Disease

Several studies on polycystic kidney disease (PKD) have revealed a number of extracellular matrix (ECM) abnormalities, suggesting that an abnormal ECM plays a role in the development of tubular cysts. Cystic kidney tubules synthesize and secrete high levels of metalloproteinases (MMP), which may participate in the restructuring of the tubular basement membrane. The aim of the present study was to determine whether serum MMP-1, tissue inhibitor of metalloproteinase (TIMP)-1, and type IV collagen levels, and plasma MMP-9 levels were altered in patients with PKD. Sixteen patients with autosomal dominant polycystic kidney disease, and 20 healthy controls were included in this study. Specific enzyme immunoassays were used to measure MMP-1, MMP-9, TIMP-1, and type IV collagen levels. Serum MMP-1 (14.8 ± 3.6 ng/ml), TIMP-1 (288.6 ± 48.6 ng/ml), and type IV collagen (192.6 ± 38.8 ng/ml) concentrations, and plasma MMP-9 (90.2 ± 26.8 ng/ml) concentrations in patients with PKD were significantly higher than those in healthy controls (MMP-1; 6.6 ± 0.9 ng/ml, p < 0.01, MMP-9; 36.4 ± 12.2 ng/ml, p < 0.01, TIMP-1; 164.6 ± 22.8 ng/ml, p < 0.01, and type IV collagen; 86.6 ± 14.2 ng/ml, p < 0.001). The present results suggest that ECM abnormalities associated with cystic kidney may result from aberrant degradation as well as from abnormal synthesis of ECM components.

Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy.

The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.

Effect of Plasma Exchange on Serum Tissue Inhibitor of Metalloproteinase 1 and Cytokine Concentrations in Patients with Fulminant Hepatitis

Aims: The present study assessed whether the serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and cytokines are altered in patients with fulminant hepatitis and whether plasma exchange affects these concentrations. Methods: Fifteen patients with fulminant hepatitis, 14 patients with severe acute hepatitis, and 20 healthy controls were included in this study. The serum levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), transforming growth factor beta (TGF-β), and TIMP-1 were determined in all patients upon hospital admission and before and after a single course of plasma exchange in the patients with fulminant hepatitis. Results: Ten out of the 15 patients with fulminant hepatitis and all patients with severe acute hepatitis survived. Serum TNF-α, IL-6, TGF-β, and TIMP-1 levels in patients with fulminant hepatitis were significantly higher than the levels in patients with severe acute hepatitis (p < 0.01). IL-1β was not detectable in either group. Plasma exchange reduced the increased serum concentrations of TNF-α, IL-6, TGF-β, and TIMP-1 in patients with fulminant hepatitis (p < 0.01). Conclusions: These data suggest that increased serum levels of TIMP-1 and cytokines may reflect severe hepatic inflammation and that plasma exchange is an effective therapy to reduce these levels.

Hemoperfusion with Polymyxin B-Immobilized Fiber in Septic Patients with Methicillin-Resistant Staphylococcus aureus-Associated Glomerulonephritis

Background/Aims: We investigated whether urinary podocytes are present in septic patients with methicillin-resistant Staphylococcus aureus (MRSA)-associated glomerulonephritis and whether polymyxin B-immobilized fiber (PMX-F) treatment affects proteinuria and urinary podocyte excretion in these patients. Methods: Twenty septic patients with MRSA-associated glomerulonephritis (mean age: 63.7 years) and 80 septic patients whose MRSA infection was not followed by glomerulonephritis (mean age: 60.5 years) were included in this study. All septic patients were treated with fosfomycin sodium, β-lactams, arbekacin sulfate, and teicoplanin, or a combination of these. Twenty septic patients with MRSA-associated glomerulonephritis were randomly assigned to one of two treatments: PMX-F treatment (group A, n = 10) and conventional treatment (group B, n = 10). PMX-F treatment was repeated twice. Results: Urinary podocytes and urinary protein excretion were not detected in MRSA septic patients without glomerulonephritis. However, urinary podocytes (1.7 ± 0.6 cells/ml) and proteinuria (2.6 ± 0.6 g/d) were detected in the 20 septic patients with MRSA-associated glomerulonephritis. Plasma endotoxin levels were decreased from 13.6 ± 4.6 pg/ml to 6.6 ± 2.2 pg/ml (p < 0.05) in group A. Levels in group B, however, showed little difference after treatment. Urinary podocytes were reduced in group A (from 1.8 ± 0.6 cells/ml to 0.4 ± 0.2 cells/ml, p < 0.01) as was urinary protein excretion (from 3.0 ± 0.5 g/d to 0.8 ± 0.4 g/d, p < 0.01) but urinary podocytes and protein excretion levels showed little difference after treatment in group B. Conclusion: PMX-F treatment may be effective in reducing urinary protein and urinary podocyte excretion in septic patients with MRSA-associated glomerulonephritis.

Hemoperfusion with polymyxin B immobilized fibers for urinary albumin excretion in septic patients with trauma.

We investigated whether microalbuminuria/urinary creatinine ratio (MACR) is increased in septic patients with trauma and whether polymyxin B immobilized fiber (PMX-F) treatment decreases MACR. Twelve trauma patients without sepsis, 18 trauma patients with sepsis, and 10 healthy controls were included in this study. The 18 trauma patients with sepsis were randomly assigned to one of two groups, PMX-F treatment or conventional treatment. Urinary microalbumin and creatinine were measured before and after treatment. Plasma endotoxin levels were determined by endospecy test. Hemoperfusion with PMX-F was carried out twice, for 2 hours, at a flow rate of 100 ml/min. MACR increased in the 30 trauma patients (5.2 ± 2.2 mg/mmol) in comparison to that in the healthy controls (1.0 ± 0.6 mg/mmol, p < 0.01). In the 18 trauma patients with sepsis, MACR after sepsis (16.6 ± 4.8 mg/mmol) was significantly greater than that before sepsis (5.5 ± 2.3 mg/mmol, p < 0.01). There was a significant correlation between plasma endotoxin levels and MACR in septic trauma patients (p < 0.001). MACR was reduced from 17.0 ± 5.0 mg/mmol to 4.2 ± 1.5 mg/mmol (p < 0.01) with PMX-F, and plasma endotoxin levels were also reduced from 34.5 ± 18.5 pg/ml to 10.8 ± 6.6 pg/ml (p < 0.01). Neither MACR nor plasma endotoxin levels were affected by conventional treatment, however. In summary, trauma patients with sepsis appear to show increased MACR, and PMX-F therapy may be effective for attenuating the increase in MACR.