Tsutomu Sanaka

Therapeutic Effects of Oral Sorbent in Undialyzed Uremia

The present study was carried out to clarify whether an oral sorbent, AST-120 (Kureha Chemical Ind Co, Tokyo), may postpone the initiation of dialysis therapy. The subjects were randomly divided into two groups, control and AST. The AST group consisted of 27 undialyzed uremic patients. Serum creatine concentrations (SCr) were 4.3 to 8.1 mg/dL (5.8 +/- 1.1 mg/dL, mean +/- SD). The control group consisted of 24 uremic patients who were not given AST-120 during the conservative therapy period before the initiation of hemodialysis. AST-120 (3.2 to 7.2 g/d) was administered to the patients in the AST group for 2.4 to 30.1 months (13.2 +/- 7.4) before the initiation of hemodialysis. The slopes of reciprocal creatinine v time in the control group were -1,251 +/- 856 x 10(-5) dL/mg/month during the 6 to 12 months before the initiation of dialysis therapy, and in the AST group, they were -1,004 +/- 1,012 x 10(-5) dL/mg/month before administration, and -347 +/- 509 x 10(-5) dL/mg/month after administration of AST-120 (P less than 0.01). All 24 patients in the control group and 21 of 27 in the AST group were introduced to hemodialysis. SCr and serum urea nitrogen (SUN) at the initiation of hemodialysis did not differ between the control and AST group: 10.8 +/- 2.6 and 11.0 +/- 2.2 mg/dL and 92.7 +/- 22.2 and 94.1 +/- 21.6 mg/dL, respectively. The times to the 50% undialyzed level were 5.0 months in the control group, and 14.3 months in the AST group.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma Pentosidine Levels Measured by a Newly Developed Method Using ELISA in Patients with Chronic Renal Failure

The plasma pentosidine levels in patients with renal disease were measured by a simple method which was established for plasma and urinary pentosidine determinations. The method, which can be completed within a few hours, involves pretreating plasma with proteolytic enzyme (pronase) and measuring the concentration of pentosidine in the sample by ELISA using antipentosidine antibodies. The prepared antibodies showed no cross-reaction with the raw materials for pentosidine synthesis or with compounds having similar structures. SDS-PAGE indicated that the antibodies had a high purity. The reaction of the antibodies and keyhole limpet hemocyanin-pentosidine in the competitive ELISA system was inhibited by free pentosidine. Excellent standard curves for pentosidine determination were obtained. In actual measurements of clinical samples from patients, a good correlation (r = 0.9356) was obtained between the values measured by ELISA and HPLC. The plasma pentosidine level in patients with renal disease correlated significantly with plasma creatinine, urea nitrogen, β2-microglobulin, and creatinine clearance, indicating its usefulness in evaluating the severity of renal disease. A significant elevation in plasma pentosidine levels was observed in mild renal dysfunction, whereas no significant increases in creatinine and urea nitrogen levels were detected, suggesting that the plasma pentosidine level is useful in the early diagnosis of beginning renal failure. In patients with chronic renal failure, no difference in plasma pentosidine levels was observed between diabetic nephropathy and chronic glomerulonephritis, while a significant correlation was observed with phosphatidylcholine hydroperoxide, suggesting the possibility that the plasma pentosidine level reflects injury due to oxidation. From these results, the quantitative measurement method developed by us is judged to be a superior innovation for measuring pentosidine in body fluids. The plasma pentosidine level may be useful for the early diagnosis of mild renal failure and to estimate the degree of the severity of renal diseases.

Protective Effect of an Oral Adsorbent on Renal Function in Chronic Renal Failure: Determinants of its Efficacy in Diabetic Nephropathy

Abstract:  Large‐scale clinical trials have shown that the oral adsorbent AST‐120 improves renal function and delays the initiation of dialysis in chronic renal failure (CRF) secondary to chronic glomerulonephritis. If renal failure progresses via common mechanisms, then the same effects can be expected in diabetic nephropathy. However, no study on diabetic nephropathy has been reported. Thus, we enrolled patients with statistically significant progression of CRF secondary to diabetic nephropathy, and analyzed the changes in renal function after AST‐120 therapy, and the clinical factors associated with response to therapy. We enrolled 276 patients with diabetic nephropathy, whose serum creatinine (Scr) had increased from 3.4 to 4.5 mg/dL during the 4.5 ± 3.7 months prior to the study. These patients took AST‐120 at a dose of 5.0 ± 1.4 g/day for 6 months. The clinical data were analyzed by dividing the patients into three groups based on the changes in Scr after AST‐120 therapy, with responders showing a decrease (N = 82), partial responders showing <1.5‐fold increase (N = 144), and non‐responders showing ≥1.5‐fold increase (N = 50). AST‐120 significantly lowered the slope of 1/Scr–time line, suggesting that AST‐120 suppressed the progression of renal impairment. No responders required dialysis, whereas 24.3% of the partial responders and 36.0% of the non‐responders started dialysis therapy. In responders, the 1/Scr–time slope showed a negative‐to‐positive shift and serum urea nitrogen decreased significantly, whereas the improvement was moderate in partial responders and minimal in non‐responders. Among responders, AST‐120 therapy significantly improved renal function despite the presence of hypoproteinemia, hyperlipidemia, anemia or hypertension in many patients. The beneficial effect of AST‐120 was significantly more marked in patients with blood pressure controlled within the normal ranges and hematocrit maintained at 30% or above. AST‐120 reversed renal dysfunction or delayed the initiation of dialysis therapy in patients with progressive aggravation of CRF secondary to diabetic nephropathy, independent of hypoproteinemia, hyperlipidemia, anemia and hypertension. Active use of AST‐120 may be recommended in patients with good control of blood pressure and hematocrit above 30%.

IGF-I as an Early Indicator of Malnutrition in Patients with End-Stage Renal Disease

The present study was performed to clarify the possibility of IGF-I as an early indicator of malnutrition in patients with end-stage renal disease. Thirty-two patients (19 males, 13 females; mean age

Effects of endothelin on renal regional blood flow in dogs.

The effects of intrarenal infusion of endothelin on renal blood flow were investigated in anesthetized dogs. Endothelin produced a biphasic change in the renal blood flow (RBF): an initial, transient increase followed by a marked, long-lasting decrease. The changes in the RBF were parallel to those in the renal cortical blood flow, whereas the changes in the medullary blood flow were less prominent. These results suggest that endothelin affects RBF, preferentially in the renal cortex.

Losartan Elevates the Serum High-Molecular Weight-Adiponectin Isoform and Concurrently Improves Insulin Sensitivity in Patients with Impaired Glucose Metabolism

Adiponectin is an adipocyte hormone that ameliorates insulin resistance and prevents diabetes. Patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are at a high risk of developing diabetes and cardiovascular diseases. Since treatment with angiotensin II receptor blockers retards the development of diabetes, the effects of losartan on serum adiponectin levels were examined with regard to insulin sensitivity in pre-diabetic patients. Sixty-five patients with IFG/IGT (42 males, 23 females, 63±13 years old) were randomized to receive 25–100 mg of losartan (n=33) or a calcium channel blocker (CCB, n=32) for 3 months. Before and after the treatment, changes in blood pressure, insulin sensitivity (HOMAR) and serum concentrations of high molecular weight (HMW)-adiponectin and free fatty acid (FFA) were assessed. At baseline, the HMW-adiponectin concentration negatively correlated with the patients body mass index, HOMA-R and triglyceride levels, and positively correlated with high-density lipoprotein (HDL)- cholesterol levels. However, the HMW-adiponectin concentration showed no correlation with blood pressure. HMW-adiponectin concentrations were similar between the losartan group and the CCB group. Both the losartan and CCB treatments similarly and significantly reduced the mean blood pressure (107±7 mmHg to 95±7 mmHg, p<0.0001, and 104±6 mmHg to 93±9 mmHg, p<0.0001, respectively). Losartan treatment resulted in a significant increase in HMW-adiponectin concentrations (45.9%) and a significant decrease in HOMA-R (23.9%) and FFA concentrations (26.5%); the percent changes were greater than those induced by CCB treatment (p<0.001, p<0.05 and p<0.01, respectively). We conclude that losartan increases the serum HMW-adiponectin concentration and concurrently improves insulin sensitivity in subjects with IFG/IGT. These results suggest that losartan may prevent diabetes by increasing serum adiponectin levels.

Effects of Glucose and Plasminogen Activator Inhibitor-1 on Collagen Metabolism in the Peritoneum

Abstract:  Nonphysiological solutions containing high glucose levels have been considered an important factor in the etiology of fibrotic changes in long‐term continuous ambulatory peritoneal dialysis (CAPD) patients. At the same time, increased Plasminogen Activator Inhibitor (PAI)‐1 secretion has been reported to correlate with fibrotic changes. We suspected that the high glucose content of peritoneal dialysis solution may induce peritoneal sclerosis via up‐regulation of PAI‐1 gene expression. In this study, we evaluated the effects of glucose on PAI‐1 activity in peritoneal fibrosis in a rat model of CAPD. The effects of glucose on the expressions of PAI‐1 and several other genes correlated with collagen metabolism were also examined in cultured rat peritoneal mesothelial cells and fibroblasts. Sprague‐Dawley rats were intraperitoneally injected twice daily for 28 days with phosphate‐buffered saline (PBS) (control group), PBS containing 4% glucose (glucose group), or PBS containing 4% glucose plus a PAI‐1 inhibitor (PAI‐1 inhibitor group). Thickening of the peritoneum with increase the deposition of collagens type I and III in the submesothelial interstitium were observed in the glucose and the PAI‐1 inhibitor group, but these were less severe in the PAI‐1 inhibitor group. Glucose stimulated expression of the mRNA of PAI‐1, collagen type I and III, and tissue inhibitor of metalloproteinase (TIMP)‐1 in fibroblasts but not in mesothelial cells. Glucose stimulated matrix metalloproteinase (MMP)‐13 mRNA expression in both cell types. The PAI‐1 inhibitor suppressed expression of the mRNAs induced by glucose. In conclusion, glucose induces peritoneal fibrosis, including changes in collagen metabolism, by stimulating PAI‐1 expression.

Reduction of Neutrophil Activation by Vitamin E Modified Dialyzer Membranes

Background/Aim: Transient leukopenia during hemodialysis due to neutrophil activation is attributed to bioincompatibility of the dailysis membrane, but the mechanism remains unclear. We studied the mechanism of neutrophilic activation by comparing a vitamin E modified membrane (CLEE) and a regular cellulose membrane (CLSS). Methods: (1) CLSS and CLEE membranes were used in a crossover clinical study in 7 chronic hemodialysis patients. Neutropenia, CD11b expression, and plasma C3a and myeloperoxidase concentrations were compared between the two dialyzer membranes. (2) Normal blood was circulated through CLEE and CLSS minimodels, and the same parameters were compared. (3) Blood samples with modified complement activities (EDTA: both classical and alternative pathways inactivated; EGTA+Mg: classical pathway inactivated; heating: alternative pathway inactivated; control: no modification) were incubated in the CLSS minimodel, and the neutrophilic activation was compared. Results: In clinical hemodialysis, neutropenia, CD11b expression, and C3a and myeloperoxidase levels were significantly lower when CLEE membranes were used. The same tendency was observed in minimodels. However, the degrees of inhibition in clinical dialysis, especially at the venous line, were significantly higher than in minimodels. As compared with controls, CD11b expression and myeloperoxidase level were significantly lower when both classical and alternative pathways were inactivated or when the classical pathway alone was inactivated, but were not significantly different when the alternative pathway alone was inactivated. Conclusions: Vitamin E modification of the dialyzer reduces some reactions of neutrophilic activation, such as CD11b expression and myeloperoxidase release, more effectively in the clinical situation than in ex vivo models, suggesting a possible effect of vitamin E in inhibiting bioreactions due to pyrogen in the dialysate. The classical complement pathway is required in membrane-induced neutrophilic activation, at least during the initial stage.

Suppressive Effect of Quinolinic Acid and Hippuric Acid on Bone Marrow Erythroid Growth and Lymphocyte Blast Formation in Uremia

The empirical treatment of chronic renal failure with dialysis therapy has achieved considerable success. But, there are some problems remaining unsolved in the management of dialysis therapy. Anemia is one of these problems.

Development of a new method for monitoring blood purification: The blood flow analysis of the head and foot by laser Doppler blood flowmeter during hemodialysis

The management of blood pressure in hemodialysis patients greatly affects not only their quality of life, but also the duration of dialysis (dialysis life). Approximately 25% of dialysis patients suffer from continuous low blood pressure; however, the relationship between blood pressure and blood flow during dialysis has not been established. We hypothesized that with complete extracorporeal circulation, blood purification methods might affect blood flow, resulting in a change in blood pressure. The purpose of this study was to develop a noninvasive continuous monitoring method (NICOMM) as a microcirculation monitor by devising a laser‐Doppler flowmeter (LDF) system with a wavelength of 780 nm. The aim was to use this system to simultaneously measure blood flow rate in both the head and the foot during dialysis and to determine the effectiveness of NICOMM by measuring blood flow and arterial distensibility. When exhibiting a significant decline in blood pressure at 240 min after the initiation of hemodialysis, a drop in blood flow in parallel with the blood pressure fall was recorded by the LDF. However, no changes were observed, in the readings by a continuous hematocrit monitor (Crit‐Line monitor, CLM). Furthermore, a significant correlation was registered between mean arterial blood pressure and blood flow rate in the earlobe tissue from 180 min after the initiation of hemodialysis to the completion of hemodialysis (p < 0.001, r = 0.78). Comparisons were made by measuring vascular dehydration using the CLM. NICOMM showed more stable readings than the CLM in monitoring blood flow in response to changes in blood pressure.