Terumi Higuchi

Dialysis-membrane-dependent reduction and adsorption of circulating hepatitis C virus during hemodialysis.

Background/Aims: Patients on chronic hemodialysis (HD) are often infected with hepatitis C virus (HCV), a common cause of chronic liver disease. In some cases, however, decreases in the serum HCV load after HD have been documented. To better understand this phenomenon, we investigated the effects of various types of dialysis membrane on virus load in the circulation in vivo and in vitro. Methods: HCV RNA levels in patients’ serum, filtrate and dialyzer membranes were analyzed semiquantitatively by reverse transcription-polymerase chain reaction (RT-PCR) before and after HD treatment with two to four different types of dialysis membrane. HCV RNA was also determined from each fraction in in vitro dialysis and ultrafiltration. Results: In HD patients treated with a polysulfone (PS) membrane and a hemophan membrane, the HCV RNA titer reproducibly decreased by a factor of 10–1–10–2. In contrast, a cuprophan (CU) membrane had no detectable effect on HCV viremia, and HD with the AN69 membrane reduced HCV RNA levels in only a subset of the patients. In addition, a PS membrane, but not a CU membrane, reduced the level of circulating HCV in an in vitro assay. In both in vivo and in vitro experiments, HCV RNA was recovered from the PS membrane itself, but not from the ultrafiltrate. Conclusions: Membrane-dependent adsorption of HCV occurs during HD, causing a transient reduction in HCV in the circulation of patients.

The dipeptidyl peptidase-4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis

Objectives: The potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. In this study, the efficacy and safety of alogliptin in type 2 diabetic patients undergoing hemodialysis (HD) were evaluated. Methods: A prospective, open-label study of 30 patients (male/female: 24/6; mean age: 69.7 ± 1.7 years) with type 2 diabetes who were undergoing HD without insulin injection therapy was conducted. Patients were administered 6.25 mg/day alogliptin and efficacy and safety were determined by monitoring clinical and laboratory parameters during the 48-week study period. Results: After 48 weeks, alogliptin had decreased postprandial plasma glucose levels from 212 ± 8 mg/dL baseline to 156 ± 7 mg/dL, hemoglobin A1c levels from 7.1 ± 0.2% baseline to 6.3 ± 0.2% and glycated albumin (GA) levels from 25.6 ± 0.6% baseline to 20.7 ± 0.4% (all p < 0.0001). Alogliptin efficacy did not differ according to median age or body mass index, but the GA reduction was significantly greater in the antidiabetic agents-naïve group. The magnitude of GA reduction was baseline GA-dependent, being greater at higher baseline GA levels. No serious adverse effects, such as hypoglycemia or liver impairment, were observed in any patient. Conclusion: Alogliptin as monotherapy or in combination with other oral antidiabetic agents improved glycemic control and was generally well tolerated in patients with HD over a 48-week period.

Clinical study of influenza-associated rhabdomyolysis with acute renal failure.

AIMS Influenza-associated rhabdomyolysis induces renal failure with a fatal outcome. The aim of this study is to evaluate the clinical features, diagnosis, and treatment efficacy of influenza-associated rhabdomyolysis patients with acute renal failure (ARF). MATERIALS AND METHODS The subjects included 6 patients who had presented with rhabdomyolysis and ARF due to influenza infection on admission to our university hospital and its 2 affiliated hospitals between January 2002 and February 2004. We retrospectively examined the cases. RESULTS All the patients (n = 6) were males, and none of them had received an influenza vaccine. The viruses were identified as influenza A (n = 5) and B (n = 1). Muscular weakness was observed in many cases (n = 5), whereas pain or tenderness was observed in only 1 case (n = 1). For anuric or oliguric patients (n = 4), blood purification therapy was performed, while for patients in whom the urine volume was normal (n = 2), conservative therapy was administered. CONCLUSION Careful medical attention is necessary when patients have muscle pain and weakness. Early recognition of rhabdomyolysis allows prompt institution of an appropriate therapy that includes blood purification and may minimize the renal dysfunction associated with this disorder.

Prolonged Protective Effect of Short Daily Hemodialysis against Dialysis-Induced Hypotension

Background/Aims: Short daily hemodialysis (HD) has a protective effect against dialysis-induced hypotension (DIH). We examined whether this effect extends beyond the treatment period. Methods: We analyzed clinical variables in 6 patients (5 with diabetes mellitus) who underwent conventional hemodialysis (CHD) for 4 h three times weekly for 12 weeks; then short daily HD for 2 h six times weekly for 12 weeks, and then 12 more weeks of CHD. All patients had been given vasopressors for severe DIH. Results: The severe DIH disappeared during the short daily HD. There were significant decreases in body weight (BW), cardiothoracic ratio (CTR), blood pressure (BP), normal saline solution (NSS) amount (62.8 ± 26.4 vs. 9.8 ± 7.4 ml/session, p < 0.05), frequency (0.60 ± 0.26 vs. 0.10 ± 0.07 infusions/session, p < 0.05) and postdialysis atrial natriuretic peptide (ANP) (176.8 ± 56.4 vs. 104.8 ± 42.3 pg/ml, p < 0.05). Weekly ultrafiltration volume (6.3 ± 0.9 vs. 7.9 ± 0.7 l, p < 0.05) was significantly higher during the short daily HD period than during the first CHD period. The vasopressor treatment was therefore stopped or reduced in all patients during the short daily HD period. Because DIH recurred in the second CHD period despite a significant increase in BP, the vasopressor treatment was resumed in 5 patients. BW, CTR, NSS infusion amount and frequency, or postdialysis ANP did not differ significantly between the short daily HD and second CHD periods. Conclusions: The protective effect of short daily HD against DIH lasted more than 12 weeks after the treatment ended. We therefore conclude that temporary short daily HD is useful for preventing DIH.

Increased Production of lnterleukin-1β and lnterleukin-1 Receptor Antagonist by Peripheral Blood Mononuclear Cells in Undialyzed Chronic Renal Failure

We investigated the cell content and production of IL-1beta and IL-1 receptor antagonist (Ra) by unstimulated and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) obtained from 15 undialyzed patients with chronic renal failure (CRF; estimated GFR <10 ml/min), 15 patients on chronic hemodialysis (HD) and 15 healthy controls. These cytokines were measured by ELISA. The cell content of IL-1beta in freshly obtained PBMC was not detectable in any group. In contrast, that of IL-1Ra in CRF (1,807 +/- 370 pg/ml, p < 0.05) as well as in HD (1,791 +/- 151 pg/ml, p < 0.001) was significantly higher than that of the controls (907 +/- 156 pg/ml). In unstimulated cultured PBMC, spontaneous production of IL-1beta in CRF (66 +/- 13 pg/ml, p < 0.05) and in HD (81 +/- 29 pg/ml, p < 0.05) was significantly higher than that of the controls (26 +/- 3 pg/ml). In contrast, comparison of spontaneous production of IL-1Ra in the three groups was not significantly different. In LPS-stimulated PBMC, IL-1beta production in CRF (10,896 +/- 1,359 pg/ml, p < 0.01)and in HD(11,441 +/- 1,400 pg/ml, p < 0.01) was significantly higher than that of the controls (6,117 +/- 572 pg/ml). However, IL-1Ra production by LPS-stimulated PBMC in the three groups was not significantly different. Moreover, the spontaneous IL-1Ra/IL-1beta production ratio in CRF (140 +/- 16, p < 0.01) and in HD (142 +/- 19, p < 0.01) was significantly lower than that of the controls (294 +/- 41). The present study demonstrates that cytokine production by PBMC in undialyzed CRF patients as well as in hemodialyzed patients is heightened and may induce impaired function of the immunological system before CRF patients are introduced to dialysis.

Evaluation of serum fetuin-A relationships with biochemical parameters in patients on hemodialysis

BackgroundComplications associated with atherosclerosis in dialysis patients are attracting attention. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In this study, the relation between serum fetuin-A concentration and biochemical parameters in patients on hemodialysis was investigated.MethodsForty hemodialysis patients, 22 men and 18 women, aged 57 ± 12 years; and 20 controls, 10 men and 10 women, aged 50 ± 10 years, participated in this study. We measured serum fetuin-A by enzyme-linked immunosorbent assay. The biochemical parameters of serum albumin, alkaline phosphatase, calcium, phosphate, intact parathyroid hormone, total cholesterol, triglyceride, lipoprotein (a), brain natriuretic peptide (BNP), highly sensitive C-reactive protein (hsCRP), hemoglobin, and hematocrit in whole blood were also measured before starting dialysis sessions. Other parameters included the cardio ankle vascular index, age, mean arterial pressure, total weekly urea clearance (Kt/V), smoking habit, body mass index (BMI), and duration of dialysis. These variables were included in simple regression analysis.ResultsLevels of serum fetuin-A in the hemodialysis patients (331 ± 55 µg/ml) were significantly lower than those in the healthy controls (361 ± 55 µg/ml; P < 0.05). There was a negative correlation between serum fetuin-A levels and duration of dialysis (r = −0.37, P < 0.01), BNP (r = −0.37, P < 0.001), and hsCRP (r = −0.40, P < 0.01), and a positive association with serum albumin (r = 0.31, P < 0.05).ConclusionsThese data suggest that a low fetuin-A level is a useful predictor of malnutrition and inflammation, as well as being a useful predictor of the cardiac failure caused by an increased ventricular load in hemodialysis patients.

A Comparison of Bicarbonate Hemodialysis, Hemodiafiltration, and Acetate-free Biofiltration on Cytokine Production

Abstract:  Acetate‐free biofiltration (AFB) is a special hemodiafiltration (HDF) modality performed with a base‐free dialysate and simultaneous injection of non‐pyrogenic sodium bicarbonate solution. The purpose of this study was to investigate the difference of cytokine production by conventional bicarbonate hemodialysis (BCD), standard HDF and AFB in the same patients. Eight stable hemodialysis patients were treated in random order with BCD, HDF and AFB every 4 weeks. The production of interleukin‐1β (IL‐1β) and interleukin‐1 receptor antagonist (IL‐1Ra) by peripheral blood mononuclear cells (PBMC) was investigated without stimulation and with stimulation by a small amount of endotoxin (ET)‐contaminated β2‐microglobulin (β2M) and lipopolysaccharide (LPS) before and after dialysis treatment in the last sessions during all periods. To serve as controls, 14 healthy volunteers participated in this study. In spontaneous IL‐1Ra production, the values of before and after AFB were not significantly different from that of the controls, and the values of before and after BCD and before HDF were significantly higher than that of the controls. In LPS‐stimulated PBMC, IL‐1β production before and after AFB was not significantly different from that of the controls, and before and after BCD and HDF was significantly higher than that of the controls. In ET‐contaminated β2M‐stimulated PBMC, IL‐1β production before and after AFB was not significantly different compared to the controls, and the production was significantly lower than that before and after BCD and HDF. In addition, IL‐1Ra production after AFB was not significantly different from the controls, and the production was significantly lower than that before and after BCD and HDF. It was concluded that a lower cytokine production by AFB may have the effect of preventing dialysis‐related complications.

Relationship between Insulin Resistance and Uremic Toxins in the Gastrointestinal Tract

The relationship between insulin resistance and local uremic toxins was examined using an oral adsorbent. Fourteen rats demonstrating a diabetic state underwent two-thirds, nephrectomy and were divided into two groups. The control group was fed standard rat chow, and the test group was fed standard rat chow containing 5% AST-120. The target level of blood glucose was achieved by controlling the dosage of exogenous insulin. All rats were sacrificed at week 6. Body weight, blood glucose level, and renal function at week 6 were not significantly different between both groups. However, the mean blood glucose level and the mean dose of exogenous insulin in the AST-120-fed group were significantly reduced as compared with the control group. The results of the present study indicate that administration of an oral adsorbent in diabetic nephropathy decreases the doses of exogenous insulin and improves insulin resistance, and that uremic toxins which exist in the gastrointestinal tract play important roles.

Chronic Effects of Long-Term Acetate-Free Biofiltration on the Production of lnterleukin-1β and lnterleukin-1 Receptor Antagonist by Peripheral Blood Mononuclear Cells

The production of interleukin-1beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1Ra) by peripheral blood mononuclear cells (PBMC) was examined in patients on long-term acetate-free biofiltration (AFB). Five stable patients on AFB were switched to bicarbonate hemodialysis (BCD) for a 2-week period using the same AN69 membrane dialyzer. IL-1beta and IL-1Ra production was measured by ELISA before and after dialysis in the last session of both treatments. Cytokine production by unstimulated PBMC did not differ significantly before and after both AFB and BCD. However, the spontaneous IL-1Ra/IL-1beta production ratio in AFB was significantly higher than that in BCD. These findings indicate that AFB may have more beneficial effects on cytokine production by PBMC compared to BCD.

Effects of Levocarnitine on Brachial-Ankle Pulse Wave Velocity in Hemodialysis Patients: A Randomized Controlled Trial

Background and Aims: Atherosclerotic cardiovascular disease is the most common cause of mortality in patients with end-stage kidney disease. Chronic kidney disease patients often exhibit a deficiency in l-carnitine due to loss during hemodialysis (HD). We studied the effects of l-carnitine supplementation on brachial-ankle pulse wave velocity (baPWV), a marker of atherosclerosis, in HD patients. Methods: This was a prospective, open-label, randomized, parallel controlled, multi-center trial testing the anti-atherosclerotic efficacy of oral l-carnitine administration (20 mg/kg/day). HD patients (n = 176, mean age, 67.2 ± 10.3 years old; mean duration of HD, 54 ± 51 months) with plasma free l-carnitine deficiency (<40 μmol/L) were randomly assigned to the oral l-carnitine group (n = 88) or control group (n = 88) and monitored during 12 months of treatment. Results: There were no significant differences in baseline clinical variables between the l-carnitine and control groups. l-carnitine supplementation for 12 months significantly increased total, free, and acyl carnitine levels, and reduced the acyl/free carnitine ratio. The baPWV value decreased from 2085 ± 478 cm/s at baseline to 1972 ± 440 cm/s after six months (p < 0.05) to 1933 ± 363 cm/s after 12 months (p < 0.001) of l-carnitine administration, while no significant changes in baPWV were observed in the control group. Baseline baPWV was the only factor significantly correlated with the decrease in baPWV. Conclusions: l-carnitine supplementation significantly reduced baPWV in HD patients. l-carnitine may be a novel therapeutic strategy for preventing the progression of atherosclerotic cardiovascular disease.