Ryuichi Furuya

Association of the serum leptin concentration with weight loss in chronic hemodialysis patients

Circulating leptin, which is partly cleared by the kidney, has been reported to increase with chronic renal failure and thus may play a role in the weight loss of patients with chronic renal failure. We investigated the association of body weight loss with the serum leptin concentration in Japanese hemodialysis patients. The relationship between serum leptin and the body mass index (BMI) or body fat mass was compared among 181 patients undergoing hemodialysis and 185 control subjects. There was no difference in the serum leptin concentration between the hemodialysis patients (HD) and controls (C) for either the men (3.9 +/- 0.2 ng/mL for HD, n=117; 3.9 +/- 0.3 ng/mL for C, n=89; NS) or women (8.9 +/- 1.2 ng/mL for HD, n=64; 7.4 +/- 0.5 ng/mL for C, n=96; NS), whereas BMI of the hemodialysis patients was significantly lower than that of the controls for both the men (20.1 +/- 0.2 kg/m2 for HD, 22.4 +/- 0.3 kg/m2 for C, P < 0.001) and women (19.2 +/- 0.3 kg/m2 for HD, 22.0 +/- 0.4 kg/m2 for C, P < 0.001). The serum leptin/body fat mass ratio was significantly correlated with the weight change of the patients during a follow-up evaluation period of 17 months (r = -0.37, P < 0.05 for men, n=27 and r = -0.53, P < 0.005 for women, n=28), indicating the possibility that a relatively high level of serum leptin had induced weight loss in the hemodialysis patients. The serum leptin/body fat mass ratio also showed a significant inverse correlation with the duration of hemodialysis (r = -0.31, P < 0.05 for men and r = -0.49, P < 0.05 for women). A multiple regression analysis indicated that the body fat mass was significantly correlated with serum leptin concentration, whereas the fat distribution did not have any relationship with leptin. These data indicate that a high level of serum leptin relative to the body fat mass might be associated with weight loss in long-term hemodialysis patients. The serum leptin level relative to the body fat mass also seems to have been affected by the duration of hemodialysis.

Ultrapure Dialysate Reduces Plasma Levels of β2-Microglobulin and Pentosidine in Hemodialysis Patients

Background: β2-Microglobulin (β2MG) and carbonyl stress are reported to contribute to the development of dialysis-related amyloidosis. The aim of this study was to determine whether the purity of dialysate affects plasma levels of β2MG and pentosidine (a surrogate marker of carbonyl stress) in hemodialysis patients. Methods: Sixteen patients on hemodialysis with a polysulfone membrane participated in this study. We switched the dialysate from conventional dialysate (endotoxin level 0.055–0.066 endotoxin units (EU)/ml) to ultrapure dialysate (endotoxin level <0.001 EU/ml), followed patients for 6 months, and then switched back to conventional dialysate once again. Plasma levels of β2MG, pentosidine, CRP and interleukin-6 (IL-6) were determined before the switch to ultrapure dialysate, 1 and 6 months after the switch to ultrapure dialysate, and 1 month after the switch back to conventional dialysate. Results: The switch from conventional to ultrapure dialysate significantly decreased plasma levels of β2MG, from 30.1 ± 1.4 to 27.1 ± 1.4 mg/dl (p < 0.05) and pentosidine, from 1,535.8 ± 107.5 to 1,267.6 ± 102.9 nmol/l (p < 0.01) after 1 month of use. The change of dialysate also significantly decreased plasma levels of CRP, from 0.28 ± 0.09 to 0.14 ± 0.05 mg/dl (p < 0.05) and IL-6, from 9.4 ± 2.7 to 3.5 ± 0.8 pg/ml (p < 0.01) over the 1-month period. These changes in plasma levels of β2MG, pentosidine, CRP and IL-6 were maintained over 6 months after switching to ultrapure dialysate and returned to basal levels by switching back to a conventional dialysate. Conclusions: Ultrapure dialysate decreases plasma levels of β2MG, pentosidine and inflammatory markers in hemodialysis patients. The use of ultrapure dialysate might be useful in preventing and/or treating complications of dialysis, such as dialysis-related amyloidosis, atherosclerosis and malnutrition.

Effects of icodextrin on glycemic and lipid profiles in diabetic patients undergoing peritoneal dialysis.

Aim: Icodextrin reduces glucose absorption from the peritoneal dialysate. We conducted this prospective, open-labeled, multicenter study to determine the effects of icodextrin on glycemic and lipid parameters in diabetic patients undergoing continuous ambulatory peritoneal dialysis (PD) or automated PD. Methods: Patients were recruited from 15 institutions in Japan, and a total of 51 patients (15 women and 36 men, mean age: 59 ± 10 years, median duration of PD: 13 months) were enrolled. The patients were administered an overnight or daytime dwell of 1.5 or 2.0 l of 7.5% icodextrin-containing solution. At baseline and 3, 6, 9 and 12 months after the start of icodextrin, nonfasting blood was drawn for measurement of glycated hemoglobin (HbA1C) and serum lipids. Results: During icodextrin treatment, there was no change in overall HbA1C levels compared to baseline values; however, for those with baseline HbA1C ≧6.5% (n = 22), significant decreases in HbA1C were observed. Mean total/LDL cholesterol and triglycerides were decreased significantly during icodextrin treatment, with greater decreases for patients with baseline total cholesterol ≧220 mg/dl, LDL cholesterol ≧120 mg/dl or triglycerides ≧150 mg/dl. HDL cholesterol did not differ at any time point; however, values for patients with baseline HDL cholesterol <40 mg/dl tended to increase with marginal significance. Conclusions: In the current study, switching from glucose-containing dialysis solution to icodextrin resulted in improved lipid profiles and possibly a favorable metabolic profile, particularly in patients with poor glycemic control. These hypotheses remain to be proven in controlled clinical trials.

Erythropoietin production in patients with chronic renal failure

Studies were performed to reexamine the response of erythropoietin (Epo) production to acute hypoxic stimuli in patients with end-stage renal disease (ESRD). In the absence of acute bleeding or hypoxia, the serum Epo level in ESRD was similar to that of normal subjects despite severe anemia. In 11 dialysis patients with acute bleeding, the decrease in the Hb level from 8.9 to 5.8 g/dL provoked a significant increase in serum Epo up to 52.2 times the normal value. The increase in serum Epo was associated with a significant increase in corrected reticulocyte. Systemic hypoxemia (PaO2 < 65 mm Hg) in 8 dialysis patients provoked a significant elevation in the serum Epo level up to 24.6 times the normal level. There was an inverse relationship between serum Epo and arterial PaO2 (r = -0.715). The serum Epo level in these patients declined to or near the normal value after recovery from acute hypoxic stress. These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo.

Coenzyme Q10 Administration Suppresses both Oxidative and Antioxidative Markers in Hemodialysis Patients

Background: Increased oxidative stress is associated with various complications in hemodialysis (HD) patients. Methods: We examined the effect of coenzyme Q10 (CoQ10) administration on the plasma oxidative products and antioxidant capacity in 36 HD patients for 6 months. Results: The advanced oxidation protein products (AOPP), malondialdehyde and the percentage of ubiquinone in total CoQ10 were significantly higher in HD patients than in healthy subjects before administration (0 month). Oxygen radical absorbing capacity (ORAC) and Trolox equivalent antioxidant capacity (TEAC), indicators of total antioxidant capacity, were also paradoxically higher in the HD patients at 0 month. AOPP and the percentage of ubiquinone significantly decreased during CoQ10 administration, but increased again after the discontinuation. ORAC and TEAC were also decreased during CoQ10 administration. Conclusion: The CoQ10 administration was partially effective for suppressing the oxidative stress in HD patients. The unexpected decrease of ORAC and TEAC by CoQ10 seemed to be associated with a decreased oxidative stress.

Impact of residual renal function on plasma levels of advanced oxidation protein products and pentosidine in peritoneal dialysis patients.

Background: Residual renal function (RRF) affects the survival rate and the development of cardiovascular disease in peritoneal dialysis (PD) patients. We evaluated the impact of RRF on oxidative and carbonyl stress in PD patients. Methods: Plasma advanced oxidation protein products (AOPP) and pentosidine were measured in PD patients with a urine volume of ≥300 ml/day (group A, n = 17) and <300 ml/day (group B, n = 14). AOPP and pentosidine were reevaluated after 12 months of follow-up in group A. Results: Plasma levels of AOPP and pentosidine in group A were significantly lower than those in group B. Renal creatinine clearance was inversely correlated with AOPP (p < 0.05) and pentosidine (p < 0.01). After 12 months of follow-up, no significant change was observed in AOPP and pentosidine in groups who maintained a urine volume of ≥300 ml/day, but significantly increased in groups whose urine volume decreased to less than 300 ml/day. There were significant inverse relationships between the changes in renal creatinine clearance and AOPP (p < 0.01) and pentosidine (p < 0.05). Conclusion: Loss of RRF is associated with increased plasma AOPP and pentosidine, indicating that preservation of RRF has a beneficial effect in reducing the oxidative and carbonyl stress in PD patients.

Impact of angiotensin II receptor blocker on plasma levels of adiponectin and advanced oxidation protein products in peritoneal dialysis patients.

Background: Oxidative stress and adipocytokines are reported to contribute to the pathogenesis of atherosclerosis. Though the inhibition of the renin-angiotensin system is known to have beneficial effects on atherosclerosis, the exact mechanisms for this remain to be clarified. The aim of this study was to determine the effects of angiotensin II receptor blockers (ARB) on the oxidative stress and adipocytokines in peritoneal dialysis patients. Methods: Candesartan (8 mg/day), an ARB, was administered for 3 months to 8 nondiabetic patients on peritoneal dialysis. Plasma levels of advanced oxidation protein products (AOPP) and adiponectin were measured before and 3 months after candesartan administration, and 3 months after discontinuation. Results: Plasma AOPP level decreased from 377.5 to 305.6 µmol/l (p < 0.05) following the administration of candesartan and returned to 394.6 µmol/l (p < 0.05) by 3 months after the discontinuation of the drug. Plasma adiponectin level increased from 12.5 to 18.8 µg/ml (p < 0.05) by candesartan and decreased again to 14.4 µg/ml (p < 0.05) after discontinuation. There was a significant inverse relationship between changes in plasma level of adiponectin and AOPP (r = – 0.888, p < 0.01). Conclusion: Candesartan increases plasma adiponectin level in association with the reduction of oxidative stress in peritoneal dialysis patients. Candesartan may be useful in preventing atherosclerosis in peritoneal dialysis patients.

Potassium-lowering effect of mineralocorticoid therapy in patients undergoing hemodialysis.

The present study was conducted to examine potassium lowering effect of exogenous mineralocorticoid (fludrocortisone acetate; FCA) administration to the patients with chronic renal failure undergoing hemodialysis. Fifteen patients on hemodialysis receiving FCA with its dosage gradually increased from 0 to 0.20 mg/day were observed for five successive 4-week periods. The serum potassium concentration was significantly decreased after FCA administration concomitant with the decrease of the salivary sodium to potassium ratio. Such decrease in serum potassium concentration was more significant in patients with <150 pg/ml of plasma aldosterone concentration (PAC) (low PAC group) than in those with ≧150 pg/ml of PAC (high PAC group). 0.05 mg of FCA was sufficient to lower serum potassium in low PAC group, while 0.15 mg of FCA was required for high PAC group. FCA administration did not affect serum sodium, chloride and bicarbonate concentrations. Body weight and blood pressure were not increased during the experimental periods. There were no significant changes in plasma level of glucose, insulin, epinephrine and norepinephrine. These results suggested that FCA could be effective to treat hyperkalemia without any adverse effects in patients undergoing hemodialysis.

Hypercalcemia in a Patient with B-Cell Acute Lymphoblastic Leukemia: A Role of Proinflammatory Cytokine

The complication of hypercalcemia is reported to occur only in 2.5-4.8% of patients with acute lymphoblastic leukemia (ALL). We herein report a 53-year-old female patient with early B-cell ALL, complicated with extreme hypercalcemia (15.2 mg/dL). Bone X-ray revealed osteolytic changes in many locations. Serum 1,25(OH)2vitaminD3 and parathyroid hormone (PTH) levels were suppressed below normal ranges on admission. The circulating parathyroid hormone-related protein (PTHrP) value was within a normal range (< 1.1 pmol/L). Serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and soluble IL-2 receptor were increased to 72 pg/ml, 25.3 pg/ml, and 1469 U/ml, respectively. Following the induction chemotherapy, the serum calcium level was promptly normalized accompanied with decreases in serum TNF-alpha, IL-6 and soluble IL-2 receptor values to 34 pg/ml, 6.35 pg/ml, and 737 U/ml, respectively. Serum PTHrP values remained within detectable levels. To our knowledge, this is the first case of B-cell ALL in a patient who developed hypercalcemia with elevated concentrations of TNF-alpha, IL-6, and soluble IL-2 receptor, but not related to PTHrP. High circulating proinflammatory cytokines may have contributed to development of ALL-induced osteolysis and hypercalcemia in the present case.

Inflammatory factors for hypoalbuminemia in Japanese peritoneal dialysis patients.

Hypoalbuminaemia is a common complication of peritoneal dialysis (PD), and the leakage of albumin through peritoneal membrane may be a principal reason for hypoalbuminaemia. However, the relationship between peritoneal inflammation, peritoneal transport properties and hypoalbuminaemia has not been fully elucidated.