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.

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.

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.

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.

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.

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.

Beneficial effects of olmesartan and temocapril on urinary liver-type fatty acid-binding protein levels in normotensive patients with immunoglobin A nephropathy.

BACKGROUND: Liver-type fatty acid-binding protein (L-FABP) is a clinical biomarker of tubulointerstitial damage, which plays an essential role in the progression of chronic kidney disease (CKD), including immunoglobin A (IgA) nephropathy. The effect of combination therapy with the angiotensin receptor blocker (ARB) and the angiotensin-converting enzyme inhibitor (ACEI) on CKD has not been elucidated. METHODS: Twenty-four normotensive patients with IgA nephropathy were randomly assigned to receive olmesartan 10 mg/day, temocapril 2 mg/day, or combination therapy with both drugs. Urinary levels of L-FABP as well as 8-hydroxydeoxyguanosine (8-OHdG) and protein excretion were measured before and after 3 months of treatment. The chronicity index and activity index were also assessed by histopathologic findings. RESULTS: Urinary levels of L-FABP and 8-OHdG were higher in patients with IgA nephropathy than in age-matched and sex-matched healthy controls (122.5 +/- 25.5 v 6.4 +/- 3.8 mug/g.creatinine, P < .001; and 22.6 +/- 4.4 v 4.8 +/- 1.4 ng/mg.creatinine, P < .01, respectively). Urinary levels of L-FABP were correlated with those of 8-OHdG (baseline, P = .0001; after 3 months, P = .008) and the severity of proteinuria (baseline, P = .0015; after 3 months, P = .0001). The percent reductions in urinary levels of L-FABP and 8-OHdG, protein excretion, and activity index after 3 months were greater in the combination therapy group, compared with each monotherapy group of olmesartan (P < .05) and temocapril (P < .05). CONCLUSIONS: The data suggest that a combination therapy of ARB plus ACEI has a greater beneficial effect on renal injury compared with monotherapy using ARB or ACEI in normotensive patients with IgA nephropathy.

Polymyxin B-immobilized fiber hemoperfusion with the PMX-05R column in elderly patients suffering from septic shock.

BACKGROUND: Direct hemoperfusion with the polymyxin B-immobilized fiber (PMX-20R) column has a positive effect on outcome in patients with sepsis or septic shock. The PMX-05R column has a low priming volume and has been used in pediatric patients with septic shock. The aim of the present study was to determine whether PMX-F treatment with the PMX-05R column is effective in elderly patients with septic shock. PATIENTS AND METHODS: We performed direct hemoperfusion twice with the PMX-05R column in 8 septic shock patients who were over 80 years of age. Five of the 8 patients survived. The 3 patients who died were undergoing hemodialysis for chronic renal failure, and methicillin-resistant Staphylococcus aureus was detected in all 3. RESULTS: PMX-F treatment significantly increased systolic and diastolic blood pressures (P = 0.0004 for both) and significantly reduced heart rate (P < 0.0001), the blood endotoxin level (P = 0.0011), blood IL-6 level (P = 0.039), C-reactive protein level (P < 0.0001), and white blood cell count (P < 0.0001). CONCLUSIONS: Direct hemoperfusion with the PMX-05R column is effective in ameliorating clinical and laboratory abnormalities in elderly septic shock patients.

Azelnidipine reduces urinary protein excretion and urinary liver-type fatty acid binding protein in patients with hypertensive chronic kidney disease.

BACKGROUND: Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD). METHODS: Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period. RESULTS: Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period. CONCLUSIONS: Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.

Effect of pitavastatin on urinary liver-type fatty acid-binding protein levels in patients with early diabetic nephropathy.

OBJECTIVE: Liver-type fatty acid-binding protein (l-FABP) is expressed in renal proximal tubules and is reported to be a useful marker for progression of chronic glomerulonephritis. The aim of this study was to determine whether urinary l-FABP levels are altered at various stages of diabetic nephropathy and whether pitavastatin affects urinary l-FABP levels in early diabetic nephropathy. RESEARCH DESIGN AND METHODS: Fifty-eight patients with type 2 diabetes (34 men and 24 women, median age 52 years) and 20 healthy, age-matched subjects (group E) were recruited for the study. The diabetic patients included 12 patients without nephropathy (group A), 20 patients with microalbuminuria (group B), 14 patients with macroalbuminuria and normal renal function (group C), and 12 patients with chronic renal failure but not undergoing hemodialysis (blood creatinine >1.2 mg/dl; mean 2.5 mg/dl, group D). Twenty group B patients were randomly assigned to receive 1 mg/day pitavastatin (10 patients, group B1) or placebo (10 patients, group B2). Treatment was continued for 12 months. Urinary l-FABP levels were measured by enzyme-linked immunosorbent assay. Urinary 8-hydroxydeoxyguanosine and serum free fatty acids (FFAs) were also measured in group B. RESULTS: Urinary l-FABP levels in groups A-D were 6.2 +/- 4.6 microg/g creatinine, 19.6 +/- 13.5 microg/g creatinine, 26.8 +/- 20.4 microg/g creatinine, and 52.4 +/- 46.8 microg/g creatinine, respectively. Urinary l-FABP levels in groups B-D were significantly higher than those in healthy subjects (group E, 5.8 +/- 4.0 microg/g creatinine) (group B, P < 0.05; group C, P < 0.01; group D, P < 0.01). In group B1, urinary albumin excretion (UAE) and urinary l-FABP levels were decreased after pitavastatin treatment (UAE before, 110 +/- 74 microg/min; 6 months, 88 +/- 60 microg/min, P < 0.05; 12 months, 58 +/- 32 microg/min, P < 0.01; l-FABP before, 18.6 +/- 12.5 microg/g creatinine; 6 months, 12.2 +/- 8.8 microg/g creatinine, P < 0.05; 12 months, 8.8 +/- 6.4 microg/g creatinine, P < 0.01). In group B2, UAE and l-FABP levels showed little change during the experimental period. In group B1, urinary 8-hydroxydeoxyguanosine was decreased 12 months after pitavastatin treatment (before 32.5 +/- 19.5 ng/mg creatinine, after 18.8 +/- 14.5 ng/mg creatinine, P < 0.01), but in group B2, these showed little difference during the experimental period. In both groups B1 and B2, serum FFAs showed little difference during the experimental period. CONCLUSIONS: Urinary l-FABP levels appear to be associated with the progression of diabetic nephropathy, and pitavastatin may be effective in ameliorating tubulointerstitial damage in early diabetic nephropathy.

Effect of low-density lipoprotein apheresis on urinary protein and podocyte excretion in patients with nephrotic syndrome due to diabetic nephropathy.

BACKGROUND: The aim of the present study is to determine whether low-density lipoprotein (LDL) apheresis affects proteinuria and urinary podocyte excretion in patients with type 2 diabetes and nephrotic syndrome. METHODS: LDL apheresis was performed on patients with diabetes with long-standing nephrotic syndrome, and urinary protein level and number of urinary podocytes were compared between these patients (5 men, 3 women; mean age, 54.6 years) and 10 nephrotic patients with diabetes not treated with LDL apheresis (6 men, 4 women; mean age, 56.5 years). RESULTS: LDL apheresis reduced total cholesterol (P < 0.001), LDL cholesterol ( P < 0.001), lipoprotein(a) (P < 0.001), creatinine (P < 0.05), and blood urea nitrogen (P < 0.05) levels and increased creatinine clearance (P < 0.05). The LDL apheresis group showed a significant decrease in urinary protein excretion (from 10.8 +/- 3.2 to 1.8 +/- 1.1 g/d; P < 0.001) and number of urinary podocytes (from 4.8 +/- 2.2 to 0.9 +/- 0.4 cells/mL; P < 0.01). CONCLUSION: These data suggest that LDL apheresis effectively reduces proteinuria and podocyte excretion, ameliorating renal dysfunction in patients with nephrotic syndrome caused by diabetic nephropathy.

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 microg/g Cr) than in healthy subjects (5.5 +/- 3.8 microg/g Cr) (P < 0.001). Candesartan cilexetil reduced urinary L-FABP levels from 168.5 +/- 104.5 microg/g Cr to 98.5 +/- 68.5 microg/g Cr after 3 months (P < 0.01) and to 44.6 +/- 30.8 microg/g Cr after 6 months (P < 0.001). Placebo had no effect on L-FABP levels (before, 140.5 +/- 100.5 microg/g Cr; at 3 months, 148.5 +/- 108.5 microg/g Cr; at 6 months, 150.5 +/- 110.8 microg/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.

Polymyxin B-immobilized fiber hemoperfusion with low priming volume in an elderly septic shock patient with marked endotoxemia.

An 84-year-old woman with septic shock caused by pyelonephritis is described herein. She was admitted for severe back pain and high fever. Her white blood cell (WBC) count and C-reactive protein (CRP) and endotoxin levels were elevated at 38,000/microl, 40.0 mg/dl, and 8,400 pg/ml, respectively. Her blood pressure was 80/34 mm Hg. Urinalysis revealed occult blood with innumerable WBCs. Plain abdominal radiography showed calcium stones in both kidneys. Septic shock with endotoxemia was diagnosed, and the patient was treated with antibiotics, gamma-globulin, and dopamine. However, her plasma endotoxin level remained high for 3 days. We performed direct hemoperfusion twice using a polymyxin B-immobilized fiber (PMX-F) column with a low priming volume. After PMX-F treatment, the patient's temperature decreased to 36.8 degrees C; her WBC count and CRP level decreased to 9,200/microl and 3.8 mg/dl, respectively. Her plasma endotoxin level decreased to 840 pg/ml after the first treatment and to 188 pg/ml after the second treatment. The next day, her blood endotoxin level further decreased to 32 pg/ml. Her blood pressure increased to 92/60 mm Hg after the first treatment and to 118/76 mm Hg after the second treatment. The patient was discharged on day 26 after admission. Our experience in this case suggests that PMX-F treatment with a low priming volume may be beneficial in elderly patients with septic shock and marked endotoxemia.

Polymyxin B-immobilized fiber hemoperfusion in a patient with active ulcerative colitis.

A case involving a 31-year-old woman with active ulcerative colitis is described. She suffered symptoms of infraumbilical abdominal pain, severe diarrhea, and low-grade fever that did not improve with conventional treatment, including antidiarrheal drugs and antibiotics. Ulcerative colitis was diagnosed according to endoscopic and histologic findings. She was treated with prednisolone and sulfasalazine, and her symptoms disappeared after 1 month. Sulfasalazine therapy was continued for 3 months, and the patient's condition remained stable for 4 years. Recently, she was admitted with abdominal pain, severe diarrhea, and melena. She was again treated with prednisolone and intravenous hyperalimentation, but her symptoms did not improve. Colonoscopy showed multiple ulcers with bleeding and polyposis and severe edema in the colon. In addition, she had a high blood endotoxin concentration (38.0 pg/ml; normal < 9.8 pg/ml). She underwent polymyxin B-immobilized fiber (PMX-F) hemoperfusion therapy twice. After 2 weeks, her symptoms resolved completely, colonoscopy showed disappearance of the edema, revascularization of the mucosa, and improvement of the ulcers, and blood endotoxin concentration decreased to 5.0 pg/ml. These results suggest that PMX-F treatment may be beneficial for the management of ulcerative colitis with endotoxemia.

Effect of polymyxin B-immobilized fiber on bone resorption in patients with sepsis.

OBJECTIVE: To analyze the effects of polymyxin B-immobilized fiber (PMX-F) on bone resorption in septic patients. DESIGN AND SETTING: Observational prospective study in intensive care units of a general hospital. PATIENTS AND PARTICIPANTS: 25 patients with severe sepsis and 20 healthy controls. MEASUREMENTS AND RESULTS: Septic patients were randomly assigned to two groups: PMX-F treatment group (n=15) and conventional treatment group (n=10). Total pyridinium crosslink pyridinoline (PYD) and deoxypyridinoline (DPD) in urine were determined by modified high-performance liquid chromatography. Nitric oxide production was assessed by measuring the ratio of the nitric oxide breakdown products to urinary creatinine (NOx/Cr). Plasma endotoxin levels were determined by endospecy test. The blood albumin, ionized calcium, and parathyroid hormone were also measured. PMX-F treatment was performed twice separated by 24 h. Urinary NOx/Cr, PYD/Cr, and DPD/Cr were significantly increased in septic patients compared with those in healthy controls. Blood ionized calcium in septic patients was lower than in healthy controls, while parathyroid hormone levels in septic patients were higher than in healthy controls (P<0.01). PMX-F treatment reduced plasma endotoxin, urinary NOx/Cr, PYD/Cr, DPD/Cr, and serum parathyroid hormone levels and increased blood ionized calcium significantly; however, conventional treatment did not affect these levels. CONCLUSIONS: Septic patients increased nitric oxide production and bone resorption, and PMX-F treatment is effective in reducing nitric oxide levels and bone resorption markers.

Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients.

Atherosclerosis is the major cause of morbidity and mortality in patients with type 2 diabetes, and pioglitazone has been reported to have anti-inflammatory and potential antiatherogenic effects. The aim of the present study was to determine whether pioglitazone, glibenclamide, or voglibose affects carotid intima-media thickness (IMT), pulse wave velocity (PWV), and urinary albumin excretion (UAE) in normotensive type 2 diabetic nephropathy patients. Forty-five normotensive type 2 diabetes patients with microalbuminuria were randomized to 12-month treatment with pioglitazone (30 mg/d, n = 15), glibenclamide (5 mg/d, n = 15), or voglibose (0.6 mg/d, n = 15). Pre- and posttreatment UAE, PWV, and IMT values were compared between treatment groups and a group of age-matched healthy control subjects (n = 30). Pretreatment PWV, IMT, and UAE values differed little between the 3 groups, but UAE was greater in the 45 type 2 diabetes patients (132.5 +/- 36.4 microg/min) than in the control subjects (6.2 +/- 1.8 microg/min, P < .001). IMT (0.76 +/- 0.12 mm) was significantly greater in the diabetics than in the controls (0.60 +/- 0.08 mm, P < .01). PWV (1,840 +/- 320 cm/s) was also significantly greater in the diabetics than in the controls (1,350 +/- 225 cm/s, P < .01). After 6 and 12 months, UAE, IMT, and PWV in the pioglitazone treatment group were significantly lower than those in the glibenclamide treatment group and voglibose treatment group (UAE: 6 months, P < .05 and 12 months, P < .01; IMT and PWV: 6 months, P < .05 and 12 months, P < .05). Pioglitazone, but not glibenclamide or voglibose, appears to be effective in reducing UAE, IMT, and PWV in normotensive type 2 diabetes patients with microalbuminuria.

Antineutrophil cytoplasmic autoantibody-associated rapidly progressive glomerulonephritis in a patient with primary biliary cirrhosis.

A 72-year-old woman with primary biliary cirrhosis (PBC) and antineutrophil cytoplasmic autoantibody (ANCA)-associated rapidly progressive glomerulonephritis is described. She had a 6-year history of PBC diagnosed histologically, with a positive test finding for antimitochondrial antibodies and elevated biliary enzyme activity. The myeloperoxidase-ANCA test result was negative. The patient was treated with ursodeoxycholic acid (600 mg/day) and had been stable for 6 years. She was admitted to our hospital because of general fatigue, exertional dyspnea, and peripheral edema. Her serum level of creatinine was increased (4.4 mg/dL), and her hemoglobin concentration was reduced (8.0 g/dL). The patient was diagnosed as having rapidly progressive glomerulonephritis. Test results for serum antinuclear antibody and myeloperoxidase-ANCA were positive. The diagnosis by renal biopsy was necrotizing crescentic glomerulonephritis. Prednisolone followed by methylprednisolone pulse therapy and cyclophosphamide were administered. The patient underwent plasma exchange twice weekly for 4 weeks. After 4 weeks, her serum creatinine level fell to 1.8 mg/dL, and she recovered renal function without hemodialysis. After 24 weeks, her renal function (serum creatinine level, 1.6 mg/dL) was stable.

Effects of polymyxin B immobilized fiber on urinary N-acetyl-beta-glucosaminidase in patients with severe sepsis.

Severe sepsis is known to cause multiple organ failure, including renal dysfunction. During sepsis, endotoxin targets the renal proximal tubular cells, the function of which can be evaluated on the basis of urinary N-acetyl-beta-glucosaminidase (NAG). We investigated whether urinary NAG activity is altered in patients with severe sepsis and whether treatment with polymyxin B immobilized fibers (PMX-F) affects this activity. Subjects of this study were 120 patients with severe sepsis and 60 healthy volunteers matched for age and gender. Patients were randomly assigned to one of two treatments: PMX-F treatment (n = 70) or conventional treatment (n = 50). The plasma endotoxin level was significantly reduced, from 34.6 +/- 10.2 to 6.8 +/- 2.4 pg/ml (p < 0.01) in patients treated with PMX-F, and the urinary NAG/creatinine ratio was reduced from 46.5 +/- 26.8 U/gm to 18.6 +/- 13.6 U/gm (p < 0.01). The plasma endotoxin level and urinary NAG/creatinine ratio were unchanged in patients who received conventional treatment. The increased urinary NAG/creatinine ratio in patients with severe sepsis may reflect proximal tubular dysfunction. PMX-F is effective in reducing proximal tubular dysfunction, in part owing to reduced plasma endotoxin levels.

Middle aortic syndrome diagnosed at 54 years of age--a case report.

A 54-year-old woman was admitted to our hospital because of heart failure, upper-limb hypertension, and lower-limb claudication. A loud systolic bruit was audible along the middle lower back. An arteriogram confirmed long-segment stenosis from the lower thoracic to the upper abdominal aorta with normal aortic arch. The patient was diagnosed as having middle aortic syndrome. This case was atypical because most cases of this disease are seen in children and young adults. After administration of diuretics and ACE-I, the heart failure and hypertension were both improved. However, the lower limb claudication was aggravated because of decreased blood pressure of the lower limb. In this patient, percutaneous angioplasty or surgical treatment will be required to prevent the recurrence of heart failure and to improve long-term quality of life by relief from intermittent claudication.