Osamu Oikawa

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.

Urinary angiotensin-converting enzyme 2 increases in diabetic nephropathy by angiotensin II type 1 receptor blocker olmesartan

Introduction: Angiotensin-converting enzyme 2 (ACE2) is a member of the renin–angiotensin system that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7). We evaluated the changes in urinary ACE2 levels in response to treatment with the angiotensin II type 1 receptor blocker olmesartan in diabetes patients with nephropathy. Materials and methods: This prospective, open-label, interventional study was conducted with 31 type 2 diabetes patients with nephropathy. After initial evaluation, patients received 20 mg/day olmesartan, which was increased to 40 mg/day over a 24-week period. Results: In diabetes patients with chronic kidney disease, olmesartan significantly increased urinary ACE2 levels independently of blood pressure and plasma aldosterone levels and reduced albuminuria, urinary liver-type fatty acid binding protein (L-FABP), and plasma aldosterone levels. Multivariable regression analysis revealed that the change in urinary L-FABP levels was an independent predictor of increased urinary ACE2 levels. Conclusion: Olmesartan may have the unique effect of increasing urinary ACE2 levels. However, whether this contributes to olmesartan’s renoprotective effect must be examined further.

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.

The Influence of Uremic Serum on Interleukin-1β and Interleukin-1 Receptor Antagonist Production by Peripheral Blood Mononuclear Cells

Abstract:  We investigated whether or not uremic serum has an influence on IL‐1β and IL‐1Ra production by normal peripheral blood mononuclear cells (PBMC). Four groups of subjects were divided into healthy controls and non‐dialyzed patients with chronic renal failure (CRF), patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients. We examined cytokine concentrations and cytokine production by PBMC from a normal subject at the density of 2.5 × 106 cells/mL incubated with 25% serum in the medium and serum containing polymyxin‐B or lipopolysaccharides (LPS). IL‐1Ra concentrations in the serum of the uremic groups were significantly higher than those of the controls. In IL‐1β production by PBMC in medium with both serum and serum containing polymyxin‐B, these values in the uremic groups were significantly higher than in the controls. In IL‐1Ra production with serum containing polymyxin‐B, these values in the uremic groups were significantly higher than in the controls. In contrast, in IL‐1Ra production by PBMC in medium with serum containing LPS, these values in the uremic groups were significantly lower than in the controls. It was concluded that uremic serum not only contains nonendotoxemic cytokine‐inducing substances, but also shows impaired cytokine production by PBMC in response to LPS.

Urinary ACE2 is associated with urinary L-FABP and albuminuria in patients with chronic kidney disease.

Abstract Aim. Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme since it converts angiotensin (Ang) II to Ang-(1–7). In addition, ACE2 has been detected in urine from patients with chronic kidney disease (CKD). The aim of this study was to determine the urinary ACE2 levels in patients with various stages of CKD and to identify the factors associated with the presence of ACE2. Methods. We assessed 152 patients with CKD stage G1–G4. The patients were classified according to the presence or absence of diabetes mellitus (DM) (DM group, n = 72; non-DM group, n = 80) and according to the estimated glomerular filtration rate (CKD stage G1/2 group, n = 40; CKD stage G3 group, n = 74; and CKD stage G4 group, n = 38). Parameters were urinary ACE2, urinary albumin/ creatinine ratio (UACR), urinary liver-type fatty acid binding protein (L-FABP), estimated glomerular filtration rate, and other factors determined to be associated with elevated urinary ACE2. Results. Urinary ACE2 was significantly higher in patients with diabetes (p = 0.01) and in patients with CKD stage G4 compared with stages G1–G3 (p < 0.0001). Multivariable regression analysis revealed that urinary L-FABP and UACR were significantly associated with urinary ACE2 levels, indicating that urinary ACE2 is increased in patients with diabetes and advanced stage CKD. Conclusion. ACE2 might continuously protect from both glomerular and tubulointerstitial injury during CKD progression. Taken together, urinary ACE2 might be a marker of kidney renin-angiotensin system activation in such patients.

Low-density lipoprotein apheresis for corticosteroid-resistant skin lesions caused by cholesterol crystal embolism: a case report and review of the literature

Cholesterol crystal embolism (CCE) is an arterio-arterial embolism originating from the breakdown of atherosclerotic plaques in the aortic wall. The embolism affects the skin and kidney particularly, as well as frequently affects the gastrointestinal tract and other organs. Although there are no clearly effective direct therapies for CCE, corticosteroid therapy and combination therapy with low-density lipoprotein apheresis (LDL-A) followed by corticosteroids were recently reported to be effective for renal manifestations in some cases. However, few cases offer suggestions for the treatment of skin lesions caused by CCE. We report here a case of a 58-year-old man diagnosed with CCE with skin manifestations and kidney dysfunction who achieved complete remission after LDL-A. LDL-A may be a useful treatment for CCE, particularly in cases with skin manifestations.

Randomized Controlled Trial of Darbepoetin α Versus Continuous Erythropoietin Receptor Activator Injected Subcutaneously Once Every Four Weeks in Patients with Chronic Kidney Disease at the Pre-Dialysis Stage

Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly assigned to receive subcutaneous CERA or DA once every four weeks during 48 weeks. In both groups, the rate of achievement of target Hb level changed from 70% to 100% in weeks 0 to 48, with no significant difference between the groups. Compared with week 0, the Hb level was significantly increased from week 24 in the DA group and from week 8 in the CERA group. In addition, the reticulocyte count was significantly increased from week 4 in the CERA group compared with the DA group. There was no significant difference in the levels of estimated glomerular filtration rate and iron status between both groups. Because of the small number of patients in this study, only limited conclusions can be drawn. However, the results suggest that subcutaneous administration of DA or CERA once every four weeks to predialysis patients has similar effects on achievement of target Hb levels.

Levocarnitine Injections Decrease the Need for Erythropoiesis-Stimulating Agents in Hemodialysis Patients with Renal Anemia

Aims: The aim of this study was to evaluate the efficacy of levocarnitine injection for renal anemia in hemodialysis patients. Methods: In this randomized controlled clinical trial, we randomly assigned patients on maintenance hemodialysis at our hospital to receive levocarnitine injections (n = 30) or no injection (n = 30) and monitored the patients during 12 months of treatment. In the treatment group, patients received an injection of levocarnitine 1,000 mg 3 times weekly after hemodialysis sessions. All patients received recombinant human erythropoietin as an erythropoiesis-stimulating agent (ESA). Response to ESA therapy was determined by calculating the erythropoietin responsiveness index (ERI; ESA dose·kg-1·g-1· dL-1·week-1). Results: (1) The target levels of hemoglobin and hematocrit were maintained during the study period in both the levocarnitine group and the control group. (2) The dose of ESAs required to maintain these levels decreased gradually in the levocarnitine group and was significantly lower at 6 and 12 months than at study initiation. Furthermore, the dose of ESAs was significantly lower than that in the control group at 12 months. (3) The ERI showed a significant decrease at 6 and 12 months in the levocarnitine group, with a significant difference between the 2 groups at 12 months. Conclusion: Our results suggest that levocarnitine administration can reduce the dose of ESAs required in patients with renal anemia on hemodialysis and improve the response to ESA therapy.

Randomized trial of frequent low-efficiency and short hemodialysis/hemofiltration in hemodialysis patients with acute brain injury

Purpose The aim of the study was to compare effects of frequent low-efficiency and short hemodialysis (FLESHD) and frequent low-efficiency and short hemofiltration (FLESHF) in hemodialysis (HD) patients with acute brain injury (ABI). Methods We randomly divided 13 HD patients with ABI into FLESHD (n = 6) or FLESHF (n = 7) groups. Conditions for the first to third sessions were as follows. FLESHD: intravenous administration of glycerol 400 ml/session, blood flow rate (QB) 100 ml/min, dialysate flow rate 300 ml/min, and treatment duration 2 h (HD-1). FLESHF: intravenous administration of glycerol 400 ml/session, QB 150 ml/min, substitution flow rate 10 l/session, and treatment duration 4 h (HF-1). After the fourth session, we gradually changed the conditions and stopped glycerol administration (HD-2 and HF-2). Results There were no significant differences in survival rate, consciousness level, or adverse effects during hospitalization in either group. In mixed model analysis, the level of HCO3– post FLESHF was significantly (p≤0.0001) increased compared with the level post FLESHD. However, no significant differences were seen in the levels of osmolality, in blood pressure before and after either dialysis method, or in the level of HCO3– pre dialysis. The variation in the relative ratio of BUN before FLESHF was significantly higher (p≤0.05) than the relative ratio before FLESHD in the sixth session. In the FLESHD groups, serum sodium was higher and serum potassium was lower than in the FLESHF groups. Conclusions FLESHD with glycerol under these conditions may be a better therapeutic option for managing patients with ABI, although the short-term survival rate is similar.

A Case Report of Hemodialysis Intolerance With Eosinophilia

Abstract:  We report the case of a patient who developed eosinophilia during hemodialysis and became intolerant to dialysis therapy. The patient, a 40‐year‐old woman, was initiated on hemodialysis for end‐stage renal failure caused by chronic glomerulonephritis. After starting on dialysis, her eosinophil count gradually increased. During the ninth session, she developed abdominal pain of an unknown cause after approximately 1 h of dialysis. The symptom, which persisted in the following sessions, was considered to be a dialysis‐related complication. We attempted different dialyzers and anticoagulants, but without improvement. The dialysis therapy was discontinued and steroid treatment was given. The hypereosinophilic condition improved rapidly and dialysis therapy was restarted successfully without causing abdominal pain. To investigate the cause of this problem, we measured the leukocyte count and anaphylatoxin C3a level in peripheral blood during dialysis, and compared the results before and after steroid treatment. The results showed that the significant decrease in the leukocyte count observed before steroid treatment was reduced to a mild decrease after steroid treatment. In contrast, C3a did not show a significant difference between the values obtained before and after steroid treatment. These findings suggest that eosinophilia played an important role in the etiology of dialysis intolerance and that C3a was not involved in the decrease in leukocytes under the conditions experienced by the present patient.