Toshimasa Takahashi

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.

Interleukin-6 gene expression in peripheral blood mononuclear cells from patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.

To compare the interleukin-6 (IL-6) gene expression in the peripheral blood mononuclear cells (PBMCs) and plasma IL-6 levels in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) with those in patients undergoing hemodialysis. Eleven hemodialysis patients, 10 CAPD patients, 15 non-dialyzed patients with end-stage kidney disease (ESKD), and 7 healthy controls were included in this study. PBMCs were collected by differential centrifugation. Plasma IL-6 concentration was measured by enzyme immunoassay. Plasma IL-6 levels were significantly increased in the hemodialysis and CAPD patients as compared with non-dialyzed ESKD patients and normal subjects (p < 0.01). Following hemodialysis, plasma IL-6 levels exceeded those before hemodialysis. No significant difference was found in plasma IL-6 levels in CAPD patients and in hemodialysis patients when blood was drawn before hemodialysis. Low but steady-state levels of IL-6 mRNA expression were observed in the non-dialyzed ESKD patients. The expression of IL-6 mRNA in PBMCs was significantly increased in the patients undergoing hemodialysis or CAPD as compared with the non-dialyzed ESKD patients. The PBMC IL-6 mRNA was significantly lower in CAPD patients than in hemodialysis patients (p < 0.01). A significant correlation was found between the plasma concentration of IL-6 and the expression of IL-6 mRNA in PBMCs from patients undergoing hemodialysis or CAPD (p < 0.01). The hemodialysis or CAPD procedure contributed to the increase in PBMC IL-6 mRNA expression and plasma IL-6 concentration. CAPD treatment stimulated the production of IL-6 to a lesser extent than hemodialysis treatment.

Altered Extracellular Matrix Component Gene Expression in Murine Polycystic Kidney

The DBA/2FG-pcy mouse has a form of slowly progressive kidney disease that appears similar in many respects to that seen in the autosomal dominant form of human polycystic kidney disease. This study was designed to assess how the expression of extracellular matrix component genes is regulated in a model of murine polycystic kidney disease and control DBA/2 mice at 8, 16, and 30 weeks of age. The mRNA levels encoding for collagen IV, the B1 and B2 chains of laminin, heparan sulfate proteoglycan, fibronectin, and collagens I and III increased with the progression of cystic lesions in the kidney of DBA/2FG-pcy mice. At 30 weeks of age, mRNA levels for collagen IV, laminin B1 and B2, heparan sulfate proteoglycan, fibronectin, and collagens I and III were increased 8.1-fold, 7.0-fold, 7.0-fold, 9.8-fold, 7.0-fold, 5.5-fold, and 5.4-fold, respectively, compared to those of control DBA/2 mice. An immunofluorescence study revealed the irregular staining for collagen IV, laminin, heparan sulfate proteoglycan, and collagens I and III around the cysts. These data suggest that changes in the expression of basement membrane components and interstitial collagens are associated with the development of polycystic kidney disease.

Increased interleukin 6 mRNA expression by peripheral blood T cells from patients with IgA nephropathy.

We investigated interleukin 6 (IL-6) mRNA expression in peripheral blood T-cells obtained from 36 patients with IgA nephropathy (IgAN), 36 patients with other glomerulonephritides and 24 healthy age-matched controls. The majority of patients with IgAN had increased IL-6 mRNA expression by their T cells; no IL-6 mRNA was detected in T cells obtained from patients with other glomerulonephritides or normal controls. A positive correlation was noted between the IL-6 mRNA level and quantity of protein excretion in the urine, histopathological findings, and renal function. However, there was no significant correlation between IL-6 mRNA expression and the IgA-immune complex titer, serum IgA level or blood pressure. mRNA levels in T cells obtained from patients with grade III or IV renal histopathological findings were significantly higher than in those with grade I or II histopathology. In addition, mRNA levels in T cells obtained from patients with more than 1.0 g/day proteinuria were markedly higher than those with less than 1.0 g/day proteinuria. We also studied the clinical course of 11 patients with IgAN during hospitalization. The IL-6 mRNA levels in these patients decreased gradually, as did proteinuria, after treatment. These studies suggest that abnormally regulated IL-6 mRNA expression in peripheral blood T cells may be associated with disease activity in IgAN.

Abnormal regulation of insulin-like growth factor gene expression in peripheral blood mononuclear cells from patients with IgA nephropathy.

We investigated insulin-like growth factor (IGF)-I and -II mRNA expression in peripheral blood mononuclear cells (PBMC) and T cells obtained from 31 patients with IgA nephropathy (IgAN), 43 patients with other types of glomerulonephritis and 16 health age-matched controls. The majority of patients with IgAN showed elevated IGF-I and -II mRNA expression in PBMC, while no IGF-I and -II mRNA expression was detected in PBMC obtained from patients with other types of glomerulonephritis or normal controls. In T cells obtained from IgAN, other types of glomerulonephritis and normal controls, however, IGF-I and -II mRNA expression was not detected. A positive correlation was noted between IGF-I and -II mRNA levels and urinary protein excretion. IGF-I and -II mRNA expression also correlated with the histopathological findings in the renal tissue of patients with IgAN. Sixty-nine percent of patients with more than 1.0 g/day proteinuria showed strong [more than (++)] IGF-I and -II mRNA expression in their PBMC. Eighty-one and 76% of patients with grade III and IV histopathological findings, respectively, showed strong IGF-I and -II gene expression in their PBMC. We also studied the clinical course of 11 patients with IgAN during hospitalization. The IGF-I and -II mRNA levels in these patients decreased gradually, as did proteinuria, after treatment. These studies suggest that abnormal regulation of IGF-I and -II gene expression in PBMC may be associated with the progression of IgAN and may be useful as an indicator of disease activity.

Importance of AST-120 (Kremezin®) Adherence in a Chronic Kidney Disease Patient with Diabetes

We report herein an adult case of chronic kidney disease (CKD) associated with diabetes. The patient had been treated with insulin injection for diabetes 10 years ago. At the time of his first visit to our division for further examinations, we diagnosed him as CKD: cause (C) diabetes; glomerular filtration rate (GFR) (G) G5 (estimated [e] GFR, 10.2 mL/min/1.73 m2; serum creatinine of 4.90 mg/dL); and albuminuria (A) A3 (2.62 g/gCr) by the Japanese Society of Nephrology (JSN) CGA classification. Because he had complained of severe constipation and kidney function, i.e., eGFR was not improved by previous medications, we added on a minimal dosage (2 g/day) of AST-120 (Kremezin®; ordinary dose 6 g/day). After 3 months of AST-120 therapy, eGFR was increased to 17.8 mL/min/1.73 m2 (serum creatinine of 2.90–2.72 mg/dL). Although the patient used some laxative products, he could not continue to take Kremezin and completely stopped 8 months after starting this drug. Kidney function then abruptly declined and progressed to end-stage kidney disease (ESKD). In June 2017, he was introduced to hemodialysis. It appears that the adherence of Kremezin is very important for inhibiting the progression to ESKD for patients with CKD with diabetes.