Yoshinobu Fuke

Complement‐mediated chronic inflammation is associated with diabetic microvascular complication

Chronic inflammation is characteristic of type 2 diabetes mellitus (T2DM). Obesity‐activated adipocytes release adipocytokines, which induce the secretion of proinflammatory cytokines, resulting in vascular endothelial dysfunction and organ injury. C3a is a candidate to induce tissue inflammation.

Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Serum Mannose-Binding Lectin Levels in Maintenance Hemodialysis Patients: Impact on All-Cause Mortality

Background/Aims: Mannose-binding lectin (MBL) is characteristic of an acute-phase-reacting protein like C-reactive protein (CRP). However, the prognostic value of the serum MBL level has not been examined. The aim of this study was to evaluate whether the serum MBL level can predict all-cause mortality in hemodialysis (HD) patients. Methods: A total of 131 patients without active infection, who had been on maintenance HD for at least 2 years, were included in this study. The serum MBL, high-sensitivity CRP (hs-CRP) level, nutrition markers, and biochemical parameters were measured in June 1999. The cohort was then followed prospectively for 36 months, and clinical data were recorded. Results: The MBL level of the 131 HD patients was 9.054 ± 5.115 µg/ml (mean ± SD). During the follow-up period, 18 patients (9 males and 9 females) died and 113 (64 males and 49 females) survived. The two leading causes of death were cardiovascular events (n = 6, 33.3%) and infection (n = 4, 22.2%). The serum MBL level was significantly lower among the nonsurvivors (6.596 ± 4.990 µg/ml) than among the survivors (9.445 ± 5.046 µg/ml; p < 0.05). There was a significant, although very weak, correlation between the MBL level and albumin level (p < 0.05), but there was no correlationbetween the MBL level and the hs-CRP level. The patients were divided into two groups according to the serum MBL level (<5 and >5 µg/ml). Multivariate analysis of factors predicting all-cause mortality in multivariate logistic regression analysis identified a serum MBL level <5 µg/ml as a variable that independently predicted all-cause mortality (adjusted odds ratio: 7.632; 95% CI: 2.244–25.961; p = 0.0011). Other significant and independent predictors for mortality included the hs-CRP level (every 100 µg/dl increase), hypertension and diabetes mellitus. Conclusions: Our findings suggest that the serum MBL level is a significant predictor of outcome in HD patients. HD patients with a low level of serum MBL should be carefully monitored.

Glomerular Deposition and Urinary Excretion of Complement Factor H in Idiopathic Membranous Nephropathy

Background/Aims: The complement system plays an important role in the pathogenesis of membranous nephropathy (MN). In order to elucidate the regulatory mechanism of complement activation, we demonstrated glomerular deposition and urinary excretion of complement factor H, which controls the alternative pathway and the amplification loop at the C3 step, in patients with idiopathic MN. Methods: Renal biopsy specimens from 20 patients with idiopathic MN were studied immunohistochemically using monoclonal antibodies against complement components including factor H. SDS-PAGE and Western blotting analysis of urine samples were performed, and the urinary excretion of factor H and C5b-9 were measured by quantitative sandwich ELISA. Results: Intense glomerular deposition of factor H was observed with C3b·C3c and C5b-9 at an early stage of the disease. Factor H was detected in Western blots of urine samples, but factor H-like protein 1 (FHL-1) was not. The mean level of urinary factor H was elevated (86.30 ± 21.93 U/mg urinary creatinine) in comparison to that of normal controls (4.76 ± 1.03 U/mg urinary creatinine). Urinary factor H level exhibited no correlation with clinical parameters; however, a negative correlation was found between urinary C5b-9/factor H and creatinine clearance (r = 0.662, p < 0.01). Conclusion: The source of glomerular and urinary factor H is supposedly a 150-kD protein. There was no evidence to suggest that FHL-1 is synthesized at the site of inflammation. The urinary C5b-9 to urinary factor H ratio is indicative of the degree of ongoing complement activation in the glomeruli and complement-mediated renal injury. These findings suggest that factor H contributes to the control mechanism of in situ complement activation and prevents renal damage in idiopathic MN.

Nephrotic syndrome with portal, splenic and renal vein thrombosis. A case report.

Background: Thromboembolism is known as a major complication of nephrotic syndrome, but only 4 cases of portal vein thrombosis have been reported as a complication of nephrotic syndrome. All of these 4 cases had acute symptoms, and 3 of 4 were in relapsing phase of nephrotic syndrome when thrombi were found. We describe here a case of 51-year-old woman with fresh nephrotic syndrome that was asymptomatically complicated by portal, splenic and renal vein thrombosis. Conclusion: In the presence of fresh nephrotic syndrome of minimal change, asymptomatic and widely distributed, including portal vein, thrombus formation occurred. If the clinical course shows resistance to therapy, we must consider the complication of venous thrombosis. Anticoagulant therapy with heparin and warfarin was effective and all thrombi disappeared without any other complications.

High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus

In systemic lupus erythematosus (SLE), glomerular involvement often progresses with the activity of the disease. Immune complexes and abnormal secretion of cytokines are thought to be involved in the central mechanism of the development of lupus nephritis. We investigated serum levels of interleukin 18 (IL-18), a proinflammatory cytokine, and its natural antagonist IL-18 binding protein (IL-18 BP) in 45 patients with lupus nephritis. IL-18 levels were significantly increased in patients with Class II, Class III, and Class IV lupus nephritis compared with the level in a healthy control group. However, the levels stayed within the non-significant range in Class V. IL-18 BP levels were significantly increased in patients with Class III and Class IV lupus nephritis, in which histological activity and chronicity are severe. However, IL-18 BP levels stayed within the non-significant range in Class II and Class V, in which histological markers are mild. We also compared the levels of IL-18 and IL-18 BP in patients with and without glomerular infiltration of inflammatory cells. IL-18 was increased regardless of glomerular infiltration. However, IL-18 BP was increased only in patients with glomerular infiltration. These data suggest that IL-18 levels indicate the extent of the offending inflammatory response not only in the bloodstream but also in renal tissue, and that high IL-18 BP levels indicate the severity of existing glomerular injury.

Peritonitis Associated With Pasteurella multocida: Molecular Evidence of Zoonotic Etiology

A patient on continuous cyclic peritoneal dialysis for chronic kidney disease due to type 2 diabetes mellitus developed peritoneal dialysis‐associated peritonitis induced by Pasteurella multocida that was isolated from a sample of dialysis effluent. The route of infection was unknown for this case; however, P. multocida was also isolated from a culture of a pharyngeal swab obtained from the patients cat. There was no evidence that the cat had bitten and ruptured the peritoneal dialysis tubing or bags. Pulsed‐field gel electrophoresis (PFGE) showed that the P. multocida isolated from the patient was completely identical to the strain isolated from the domestic cat. As there is a rise in the pet‐keeping population, an increase in zoonoses is to be expected. It is necessary to be carefully informed of hygiene rules in keeping pets because a pet may transmit zoonoses, even on casual contact.

Urinary complement factor H in renal disease

Background: Complement factor H (hCFH) plays a key inhibitory role in the control of the alternative complement pathway. We examined whether urinary hCFH (U-hCFH) levels is useful as an indirect indicator of renal damage. Methods: Urine samples were obtained from 104 patients with renal disease. Urine was collected with 10 mM EDTA and U-hCFH levels were measured using the BTA TRAK Assay Kit. Results: In the 62 patients with nephritis, the levels of U-hCFH were elevated (range 15–52,198 U/ml) over the normal range (0–14 U/ml). U-hCFH levels of patients with chronic renal failure, lupus nephritis, membranoproliferative glomerulonephritis, focal glomerulosclerosis were higher than that of IgA nephropathy patients (p < 0.05). In the patients with minimal change disease, showed high levels of U-hCFH during the nephrotic syndrome. U-hCFH was correlated significantly with urinary protein and urinary N-acetyl-β-D-glucosaminidase. Conclusion: We demonstrated that U-hCFH was detected in the urine of nephritis patients.

Alterations of Insulin Resistance and the Serum Adiponectin Level in Patients with Type 2 Diabetes Mellitus Under the Usual Antihypertensive Dosage of Telmisartan Treatment

BACKGROUND Insulin resistance plays a central role in the pathophysiology of diabetes complications. Angiotensin II receptor blockers (ARBs) regulate angiotensin II receptor-mediated inhibition of intracellular glucose transporter 4 translocation. Telmisartan, one of the known ARBs, was reported to improve insulin resistance via the increase of peroxisome proliferator-activated receptor gamma activity in the model animal. This study examined whether this effect was observed in diabetes patients under the usual antihypertensive dosage of telmisartan treatment. METHODS Twenty-seven diabetes patients were chosen for this prospective study. Patient blood pressures were successfully controlled for the most recent 6 months by ARBs other than telmisartan. After informed consent was obtained, we changed to telmisartan from the other ARBs. The parameters of hypertension, hyperlipidemia, glycemic control, and renal function were examined. RESULTS The values of the homeostasis model assessment of insulin resistance (HOMA-IR) improved from 7.1 +/- 1.5 to 3.8 +/- 3.6 after 3 months. The serum level of adiponectin significantly increased after 6 months. The distributions of other parameters were correlated with that of HOMA-IR or adiponectin. CONCLUSIONS The data indicate that the usual antihypertensive dosage of telmisartan improves insulin resistance and changes adiponectin effect in patients with diabetes mellitus. Adipokine-related insulin resistance and angiotensin II receptor 1-mediated insulin resistance are improved by telmisartan.

Relationship between oligomer and functional serum mannose-binding lectin in chronic renal failure

Eur J Clin Invest 2010; 40 (10): 865–873