Combination therapy with polymyxin B-immobilized fibre haemoperfusion and teicoplanin for sepsis due to methicillin-resistant Staphylococcus aureus.

The aim of the present study was to determine whether treatment with polymyxin B-immobilized fibre (PMX-F) haemoperfusion, teicoplanin, or both in combination is effective in patients with methicillin-resistant Staphylococcus aureus (MRSA) sepsis. Sixty patients with MRSA sepsis were randomly assigned to one of four treatments: (A) PMX-F treatment (N=15), (B) teicoplanin treatment (N=15), (C) PMX-F and teicoplanin in combination (N=20) and (D) conventional therapy (N=10). PMX-F treatment was repeated twice. Teicoplanin was administered by intravenous injection. Plasma endotoxin levels were determined by endospecy test. Plasma endotoxin levels were reduced in groups A and C (P<0.05). Survival rates were 53, 47, 90, and 20% in groups A, B, C and D, respectively (group C versus group A, P<0.05; group C versus group B, P<0.01; group C versus group D,P <0.001). The mean duration of stay was 44, 42, 28 and 56 days in groups A, B, C and D, respectively. Our data suggest that combination therapy with PMX-F and teicoplanin is effective for sepsis caused by MRSA.

Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative Lupus nephritis.

Intravenous cyclophosphamide (IVC) in combination with steroids is standard therapy for Lupus nephritis. Reduction of autoantibodies and circulating immune complexes can be used in the treatment of autoimmune diseases. The aim of the present study was to compare the effects of IVC pulse therapy and double-filtration plasmapheresis (DFPP) on proteinuria and urinary excretion of podocytes in adult patients with diffuse proliferative Lupus nephritis (DPLN). Twenty patients were randomly assigned to two groups. Group A (n = 10) was treated with IVC (0.75 - 1.0 g/m2 body surface area) pulse therapy, given as boluses once a month for 6 consecutive months, combined with oral corticosteroid (up to 1 mg/kg/day) administration. Group B (n = 10) was treated with a combination of DFPP (performed 1-2 times weekly) and corticosteroid (up to I mg/kg/ day). The total average number of treatments was 8.4 and the therapeutic efficacies were evaluated after 6 months. Twenty healthy individuals participated as a control group. Urinary podocytes were examined by immunofluorescence with monoclonal antibodies against podocalyxin. Both Group A and Group B reduced proteinuria (p < 0.001) as well as the number of urinary podocytes (p < 0.001). Differences between the 2 treatment outcomes were not statistically significant. Cyclophosphamide pulse therapy and DFPP may be similarly effective in the treatment of podocyte injury in patients with DPLN.

Combination therapy of trandolapril and candesartan cilexetil reduces microalbuminuria and urinary endothelin-1 excretion in patients with type 2 diabetes.

Background. Angiotensin (AT)-converting enzyme inhibitors (ACEIs) and AT1-receptor blockers (ARBs) are widely used to reduce urinary albumin excretion (UAE) and slow the progression of diabetic nephropathy. The aim of the present study was to determine whether treatment with trandolapril (an ACEI) and candesartan cilexetil (an ARB) in combination has more effect on UAE and urinary endothelin (ET)-1 excretion than treatment with trandolapril or candesartan cilexetil alone in patients with type 2 diabetes. Methods. Sixty normotensive type 2 diabetes patients with microalbuminuria were randomly assigned to four treatment groups: (A) treatreatment with trandolapril at 2 mg/day (n = 15), (B) treatment with candesartan cilexetil at 8 mg/day (n = 15), (C) treatment with trandolapril at 2 mg/day and candesartan cilexetil at 8 mg/day (n = 15), and (D) treatment with placebo (n = 15). The study period was 18 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in the patients before treatment and after 12 and 18 months of treatment. Results. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little between the four groups. Trandolapril and candesartan cilexetil administered alone reduced UAE and urinary ET-1 excretion to a similar extent (12 months; P < 0.05 and 18 months; P < 0.01). When trandolapril and candesartan cilexetil were coadministered, UAE and urinary ET-1 excretion decreased to a significantly greater extent at 12 and 18 months (P < 0.05) than with trandolapril or candesartan cilexetil alone. However, plasma ET-1 and systemic blood pressure levels were not affected. Conclusions. The data suggest that combination therapy with trandolapril and candesartan cilexetil has an additive effect on the reduction of microalbuminuria in microalbuminuric normotensive type 2 diabetes patients.

Changes in concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 in patients with paraquat poisoning.

Respiratory failure is one of the major causes of death in patients with paraquat poisoning. In paraquat-poisoned lungs, abnormal extracellular matrix regulation occurs. The aim of the present study is to determine whether serum concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) are altered during the course of paraquat poisoning and whether haemoperfusion therapy affects these concentrations. Twenty-one patients were admitted within 3 h after ingestion of paraquat and all patients received direct haemoperfusion therapy. Five out of 21 patients survived and 16 patients died within 28 days. Plasma paraquat concentrations in non-survivors (5740 +/- 380 microg l(-1)) were not significantly different from those in survivors ( 5920 +/- 280 microg l(-1)) before treatment. Haemoperfusion reduced these concentrations in both non-survivors (120 +/- 7 microg l(-1)) as well as survivors (136 +/- 9 microg l(-1)) on day 5. Serum concentrations of type IV collagen and TIMP-1 in survivors showed little change between day 1 (type IV collagen, 90.4 +/- 3.6 ng ml(-1); TIMP-1, 172.2 +/- 7.0 ng ml(-1)) and day 5 (type IV collagen, 92.6 +/- 4.2 ng ml(-1); TIMP-1, 174.2 +/- 7.2 ng ml(-1)). In contrast, these concentrations in non-survivors on day 5 (type IV collagen, 143.6 +/- 7.8 mg ml(-1); TIMP-1, 246.8 +/- 13.6 ng ml(-1)) were significantly higher than those on day 1 (type IV collagen, 88.4 +/- 4.2 ng ml(-1), P < 0.01; TIMP-1, 170.6 +/- 9.2 ng ml(-1), P < 0.05). These data suggest that serum concentrations of type IV collagen and TIMP-1 may be useful indicators for the development of respiratory failure in patients with paraquat poisoning.

Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria.

In various renal diseases, including diabetic nephropathy, detection of podocytes in the urine indicates severe injury to podocytes in the glomeruli. Pioglitazone is a newly developed antidiabetic agent that attenuates insulin resistance. The aim of the present study was to determine whether pioglitazone affects urinary albumin excretion (UAE) or the number of urinary podocytes or both in type 2 diabetes patients with microalbuminuria. Twenty-eight patients with normotensive type 2 diabetes and microalbuminuria (18 men and 10 women; mean age, 52.5 years) and 30 age-matched normotensive controls (20 men and 10 women; mean age, 51.5 years) were included in the study. Urinary podocytes were detected by immunofluorescence with a monoclonal antibody against podocalyxin. Patients were randomly assigned to 2 groups: a pioglitazone-treatment group (30 mg/day, n = 14) and a placebo group (n = 14). Treatment was continued for 6 months. Podocytes were absent in the urine of healthy controls, but detected in 17 of 28 diabetic patients (60.7%). UAE was reduced from 96.7 +/- 50.5 microg/min to 39.7 +/- 22.9 microg/min (P <.01) in the pioglitazone-treatment group, and the number of urinary podocytes was reduced from 0.9 +/- 1.0 cells/mL to 0.1 +/- 0.2 cells/mL (P <.001). Neither UAE nor the number of urinary podocytes was affected in the placebo group. These data indicate that pioglitazone is effective for reducing UAE and podocyte injury in early-stage diabetic nephropathy.

Effect of troglitazone on urinary albumin excretion and serum type IV collagen concentrations in Type 2 diabetic patients with microalbuminuria or macroalbuminuria.

AIMS: Troglitazone, a newly developed thiazolidinedione derivative, has been shown to ameliorate microalbuminuria in diabetic animal model and in human diabetic nephropathy in short-term studies. The aim of the present study was to determine whether troglitazone or sulphonylurea affect micro- albuminuria, macroalbuminuria, or serum type IV collagen concentrations in patients with diabetic nephropathy. METHODS: We studied 32 normotensive patients with type 2 diabetes mellitus associated with microalbuminuria (n = 16) or macroalbuminuria (n = 16) and 20 healthy controls. The patients were randomly assigned to one of two groups: those treated with glibenclamide (5.0 mg/day) (n = 8) and those treated with troglitazone (400 mg/day) (n = 8). They received the drug regimen for 12 months. Serum type IV collagen was measured with sandwich enzyme immunoassay. RESULTS: Type IV collagen concentrations in macroalbuminuric patients were higher than those in microalbuminuric patients (P < 0.05) and healthy controls (P < 0.01). Troglitazone reduced urinary albumin excretion (UAE) in micro-albuminuric patients from 126 microg/min (range 58--180 microg/min) to 42 microg/min (range 14--80 microg/min) (P < 0.01) and also reduced serum type IV collagen levels gradually at 3, 6 and 12 months after treatment (P < 0.05). However, glibenclamide did not affect UAE and type IV collagen levels in micro- albuminuric diabetes patients. In addition, neither troglitazone nor gliben- clamide changed UAE and type IV collagen levels in macroalbuminuric patients. CONCLUSIONS: These data suggest that troglitazone is an effective treatment for renal injury in patients with early diabetic nephropathy.

Effect of dilazep dihydrochloride on urinary albumin excretion in patients with autosomal dominant polycystic kidney disease.

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 +/- 52 to 46 +/- 26 microg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD 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 microg/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 HbA(1c) 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.

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.

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.

Urinary excretion of podocytes in patients with diabetic nephropathy.

BACKGROUND: Detection of podocytes in the urinary sediments of children with glomerulonephritis has been shown to indicate severe injury to the podocytes. The aim of the present study was to determine whether podocytes are present in the urine sediments of adult patients with diabetes with and without nephropathy and whether trandolapril is effective for podocyte injury. METHODS: Fifty diabetic patients (10 with normoalbuminuria, 15 with microalbuminuria, 15 with macroalbuminuria and 10 with chronic renal failure) and 10 healthy controls were studied. Urinary podocytes were examined by immunofluorescence using monoclonal antibodies against podocalyxin, which is present on the surface of podocytes. In addition, we studied plasma metalloproteinase (MMP)-9 concentrations in all patients. RESULTS: Urinary podocytes were absent in healthy controls, diabetic patients with normoalbuminuria and diabetic patients with chronic renal failure. Podocytes were detected in the urine of eight diabetic patients with microalbuminuria (53%) and of 12 patients with macroalbuminuria (80%). The number of podocytes in the urine of patients with macroalbuminuria was significantly greater than in patients with microalbuminuria (P:<0.01). However, there was no relationship between urinary albumin excretion and urinary podocytes. In addition, plasma MMP-9 concentrations were significantly correlated with the number of urinary podocytes (P:<0.01). Twelve diabetic patients with macroalbuminuria and eight patients with microalbuminuria who had urinary podocytes were treated with the angiotensin-converting enzyme inhibitor trandolapril. Urinary albumin excretion, the number of podocytes and plasma MMP-9 concentrations were reduced by the trandolapril treatment. CONCLUSIONS: Podocytes in the urine may be a useful marker of disease activity in diabetic nephropathy. Trandolapril may be effective for podocyte injury.

Urinary podocytes for the assessment of disease activity in lupus nephritis.

BACKGROUND: Detection of podocytes in the urine indicates that severe injury of podocytes occurred in the glomerulus in children. METHODS: The 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 IlIa, 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). RESULTS: Podocytes 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. CONCLUSIONS: These 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.