Shiwori Osada

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.

Enhanced expression of membrane type-1 matrix metalloproteinase in mesangial proliferative glomerulonephritis.

Matrix metalloproteinase-2 (MMP-2, gelatinase A) is involved in the inflammatory and sclerotic events of glomerular diseases. Newly identified membrane-type matrix metalloproteinases (MT-MMP) have been shown to activate specifically proMMP-2. To date, several types of MT-MMP have been cloned; however, their expressions in glomerular diseases have not been evaluated. To investigate the role of MT-MMP in glomerular diseases, the glomerular gene expression and enzymatic activity of MT-MMP were examined during the time course of nephritis induced in rats by anti-Thy1.1 antibody injection. Both MT1-MMP and MMP-2 mRNA expression increased prominently 5 and 10 d after anti-Thy1.1 antibody injection and decreased thereafter, as assayed by semiquantitative reverse transcription-PCR. In contrast, there were no remarkable changes in the gene expression of MT2-MMP between normal and diseased tissue, and that of MT3-MMP was not detected in isolated glomeruli by reverse transcription-PCR analysis. The activation of proMMP-2 as analyzed by gelatin zymography correlated with the glomerular MT1-MMP gene expression, suggesting that proMMP-2 was activated by MT1-MMP. Protein and mRNA expression of fibronectin, one of the major mesangial matrix proteins and substrate of MMP-2, were also synchronized with MT1-MMP and MMP-2 expression. In situ hybridization revealed intense MT1-MMP mRNA expression in the proliferating mesangial cells. Interestingly, MT1-MMP gene expression exhibited a similar distribution as alpha-smooth muscle actin expression, which was closely associated with mesangial phenotypic change. These results suggest that among the newly identified MT-MMP, MT1-MMP may play the central role in activation of proMMP-2. Furthermore, the enhancement of MT1-MMP and MMP-2 expression associated with mesangial phenotypic change may contribute to the development of anti-Thy1.1 antibody-induced glomerulonephritis and remodeling of extracellular matrices.

Macrophage-derived MT1-MMP and increased MMP-2 activity are associated with glomerular damage in crescentic glomerulonephritis.

Membrane‐type matrix metalloproteinases (MT‐MMPs) have been shown to activate pro‐MMP‐2 on the cell surface and are suggested to be key enzymes in tissue remodelling under various physiological and pathological conditions. To investigate the role of MT‐MMP in progressive renal injury, the gene expression and enzymatic activity of MT‐MMP were examined in crescentic glomerulonephritis induced by anti‐glomerular basement membrane (GBM) antibody in WKY rats. Isolated glomeruli were subjected to RNA and protein extraction 0, 1, 3, 7, 14, and 28 days after intravenous injection of rabbit anti‐GBM antibody. Semiquantitative RT‐PCR analysis revealed that among the three members of the MT‐MMP family, mRNA expression of MT2‐MMP remained unchanged and that of MT3‐MMP was not observed in glomeruli during the development of nephritis. However, MT1‐MMP gene expression increased from day 3 and reached maximum levels at day 7 (5.5±0.7‐fold increase over day 0), closely associated with macrophage accumulation, crescent formation, and increased proteinuria. Gelatin zymography showed that the active from of MMP‐2 emerged from day 7 and remained during the experimental period accompanied by increased proMMP‐2, while no active form of MMP‐2 was found in control rats. Using an antisense cRNA probe, intense signals of MT1‐MMP mRNA were observed mostly in cells within the crescent and in some cells in the mesangial areas. Most of these cells were ED‐1‐positive macrophages, based on immunostaining of sequential sections. These results suggested that in the MT‐MMP family, MT1‐MMP was induced in infiltrating macrophages during the development of crescentic glomerulonephritis and possibly contributed to pathological degradation of glomerular extracellular matrices through the activation of proMMP‐2. Copyright

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.

Candesartan Reduces Urinary Fatty Acid-Binding Protein Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease

Background:Free fatty acids (FFAs) bound to albumin are overloaded in renal proximal tubules and exacerbate tubulointerstitial damage. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of FFAs that is expressed in renal proximal tubules in humans. Urinary L-FABP reflects the clinical prognosis of chronic glomerulonephritis. The aim of the present study was to determine whether urinary L-FABP excretion is altered in patients with autosomal dominant polycystic kidney disease (ADPKD) and whether candesartan cilexetil, an angiotensin II receptor antagonist, affects these levels. Methods:Subjects comprised 20 normotensive ADPKD patients (8 men and 12 women, mean age 42.6 years) and 20 age-matched healthy volunteers (8 men and 12 women, mean age 44.0 years). The 20 ADPKD patients participated in a randomized double-blind placebo-controlled study of candesartan cilexetil for 6 months. Urinary L-FABP levels were measured by a newly established ELISA method. Results:Urinary L-FABP levels were significantly higher in ADPKD patients (154.5 ± 110.6 &mgr;g/g Cr) than in healthy subjects (5.5 ± 3.8 &mgr;g/g Cr) (P < 0.001). Candesartan cilexetil reduced urinary L-FABP levels from 168.5 ± 104.5 &mgr;g/g Cr to 98.5 ± 68.5 &mgr;g/g Cr after 3 months (P < 0.01) and to 44.6 ± 30.8 &mgr;g/g Cr after 6 months (P < 0.001). Placebo had no effect on L-FABP levels (before, 140.5 ± 100.5 &mgr;g/g Cr; at 3 months, 148.5 ± 108.5 &mgr;g/g Cr; at 6 months, 150.5 ± 110.8 &mgr;g/g Cr). During the 6 months, serum creatinine, blood urea nitrogen, 24-hour creatinine clearance and blood pressure showed little change in either group. Conclusions:Increased urinary L-FABP levels may be associated with the development of ADPKD, and candesartan cilexetil has a beneficial effect on reducing these levels.

Early induction of the NGFI-BNur77 family genes in nephritis induced by anti-glomerular basement membrane antibody

We recently isolated a novel nuclear receptor NOR-1, which is a member of the steroid/thyroid receptor superfamily, and belongs to the NGFI-B/Nur77 family. In the present study, we examined gene expression of NOR-1 and its closely related members in nephritis induced by anti-glomerular basement membrane (GBM) antibody. The mRNA levels for NOR-1, NGFI-B and RNR-1 increased 24 h after injection of anti-GBM antibody (day 1). Gene expression of NOR-1 and NGFI-B reached maximum levels on day 3, gradually decreased thereafter and returned to control levels on day 28. RNR-1 reached a peak on day 7, and then decreased. Renal injuries were most prominent on day 7 and persisted until day 28, indicating that NOR-1, NGFI-B and RNR-1 genes are induced during the early stage of glomerulonephritis and may be associated with the progression of glomerulonephritis. The induction of the NGFI-B gene was less remarkable than that of NOR-1 and RNR-1. In addition, administration of glucocorticoid hormone suppressed NOR-1 and RNR-1 gene expression to almost normal levels, whereas NGFI-B gene expression was not significantly repressed. These findings also suggest that the NGFI-B/Nur77 family may possess different biological roles and NGFI-B might act as a general transcription factor in cell function.

Evaluation of parathyroid hyperplasia by ultrasonographic examination in patients with end-stage renal failure before and at initiation of dialysis

SUMMARY:  Secondary hyperparathyroidism (2HPT), which is related to renal osteodystrophy (ROD), may occur in patients in the comparatively early stage of chronic renal failure (CRF). Secondary hyperparathyroidism patients with parathyroid hyperplasia showed resistance to vitamin D3 treatment during long‐term dialysis. At present, evaluation by ultrasonography is considered to be useful for confirming parathyroid hyperplasia. There are no clinical data associated with imaging evaluation of 2HPT in CRF patients. In the present study, the relationship among clinical and biochemical data, and parathyroid hyperplasia by ultrasonography, was evaluated in 12 patients (six males and six females) with end‐stage renal failure (ESRF) before and at initiation of dialysis. Five patients showed an enlargement of parathyroid glands in ultrasonography. Levels of serum‐intact parathyroid hormone (PTH) in patients with parathyroid hyperplasia (positive group) were significantly higher than in those without hyperplasia (negative group; 97.6 ± 36.65 vs 17.4 ± 4.45 pmol/L; P < 0.05). The levels of intact PTH were above 35.0 pmol/L in all five patients with hyperplasia. All patients in the positive group had never taken vitamin D3 supplements. Calcium‐containing phosphate binders were not prescribed before the present study, except in one patient. Parathyroid hyperplasia caused by 2HPT was recognized in patients before and at initiation of dialysis in this study. It appears that untreated 2HPT in CRF patients may progress to advanced 2HPT in ESRF before and/or after the early stage of dialysis. The levels of serum intact PTH are useful in predicting parathyroid hyperplasia.

Effect of dilazep dihydrochloride on serum cardiac troponin T levels in hemodialysis patients

Background/Aim: Cardiac troponin T is a highly sensitive marker for the detection of myocardial injury. We studied whether dilazep dihydrochloride affects cardiac troponin T levels in hemodialysis patients. Methods: Our study included 60 hemodialysis patients without symptoms of acute myocardial ischemia. We measured serum cardiac troponin T levels by the Elecsys® troponin T assay and randomized 40 hemodialysis patients with left ventricular hypertrophy (LVH) into two treatment groups: a dilazep dihydrochloride group (300 mg/day, n = 20) and a placebo group (n = 20). Treatment was continued for 12 months. Results:There were no significant differences between pre- and postdialysis cardiac troponin T levels before treatment. LVH was noted in 40 patients out of 60 hemodialysis patients (67%). Cardiac troponin T levels were significantly higher in these patients (0.23 ± 0.08 µg/l) than in hemodialysis patients without LVH (0.09 ± 0.03 µg/l). Cardiac troponin T levels were reduced from 0.24 ± 0.08 to 0.12 ± 0.06 µg/l (p < 0.01) in patients treated with dilazep dihydrochloride. There were no change in cardiac troponin T levels in patients receiving placebo (from 0.21 ± 0.08 at baseline to 0.20 ± 0.07 µg/l). Conclusion: Dilazep dihydrochloride may be effective in ameliorating myocardial damage in hemodialysis patients.