Kazuko Itoh

Vitamin D Receptor Activator Reduces Oxidative Stress in Hemodialysis Patients With Secondary Hyperparathyroidism

Treatment with a vitamin D receptor activator (VDRA) has survival benefits probably related to its effects beyond the traditional role in mineral metabolism. We hypothesized that VDRA reduces oxidative stress in hemodialysis (HD) patients. To test this hypothesis, we investigated the effect of VDRA on the oxidative status of albumin in HD patients with secondary hyperparathyroidism. Eleven HD patients with secondary hyperparathyroidism were treated with calcitriol at an intravenous dose of 1.5 µg/week for four weeks. Serum intact parathyroid hormone, calcium and phosphorus were monitored and we measured the amount of oxidized albumin and albumin hydroperoxides form before and after calcitriol treatment. The ratio of oxidized to un‐oxidized albumin was determined as a representative marker of oxidative stress. The radical scavenging activity of albumin was also evaluated. After four weeks of calcitriol therapy, there were no significant changes in serum intact parathyroid hormone, calcium, or phosphorus levels; however, the ratio of oxidized to un‐oxidized albumin was markedly decreased and serum thiol content was significantly increased after calcitriol treatment. Furthermore, the radical scavenging activity of albumin was greater after calcitriol treatment compared with that of untreated albumin. Our data suggest that intravenous calcitriol treatment reduces oxidative stress and strengthens antioxidant defenses by inhibiting albumin oxidation in HD patients with secondary hyperparathyroidism.

Association between long-term efficacy of cinacalcet and parathyroid gland volume in haemodialysis patients with secondary hyperparathyroidism.

Purpose. Secondary hyperparathyroidism with nodular hyperplasia is resistant to medical therapies. Cinacalcet is an effective treatment for severe secondary hyperparathyroidism. This multicentre retrospective study was designed to determine the long-term efficacy of cinacalcet in patients with nodular hyperplasia, the advanced type of parathyroid hyperplasia. Subjects and methods. The study subjects were 20 haemodialysis patients with secondary hyperparathyroidism. Patients with ultrasonographically confirmed large parathyroid glands (volume >0.5 cm3) were considered to have nodular hyperplasia (n = 8). Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target intact-parathyroid hormone (iPTH) level of <250 pg/ml. Serum iPTH, corrected calcium, serum phosphorus, calcium × phosphorus product were measured and compared over the 48-week period of treatment with cinacalcet in all 20 patients and over 120 weeks in 6 of the patients (2 with nodular hyperplasia and 4 with non-nodular hyperplasia). We also examined the achievement rate of K/DOQI guideline treatment targets. The dosages of vitamin D preparation, sevelamer hydrochloride and calcium- containing phosphate binder were adjusted for the above target values. Results. iPTH levels were significantly lower at 48 weeks in both groups. However, corrected calcium levels, serum phosphorus levels and calcium phosphorus products were within the target values in the non-nodular hyperplasia group (n = 12), while the target value could not be achieved in the nodular hyperplasia group. In the long-term follow-up group, the levels of iPTH, corrected calcium, serum phosphorus and calcium × phosphorus products were significantly higher in nodular hyperplasia than in non-nodular hyperplasia. Conclusion. Our study suggests that cinacalcet lacks long-term efficacy in nodular hyperplasia, especially for controlling serum calcium and phosphorus levels.

Effects of raloxifene on bone mineral metabolism in postmenopausal Japanese women on hemodialysis.

In addition to renal osteodystrophy, postmenopausal women on hemodialysis are at high risk for osteoporosis. Recent studies reported the effects of raloxifene, a selective estrogen receptor modulator for osteoporosis, in postmenopausal women. The present study evaluated the efficacy of raloxifene and its effects on bone mineral metabolism in postmenopausal Japanese patients on dialysis. In a prospective, multicentre study, 17 postmenopausal women on chronic hemodialysis with severe osteoporosis (bone mineral density [BMD]≤2 SD by bone densitometry) were treated with 60 mg/day raloxifene hydrochloride for 12 months. The study also included 10 age‐matched control women. Vitamin D and calcium salts were not changed during the study. Intact parathyroid hormone (iPTH), serum calcium and phosphorus, and bone resorption marker (NTx) were measured, and BMD were determined by DEXA, at 0, 6, and 12 months after administration of raloxifene. The mean lumbar spine BMD at baseline was similar in the two groups. Raloxifene therapy (for 12 months) improved lumbar spine BMD (by 2.6%) in 53% of the patients, while 70% of the control group showed a reduction in BMD (by 4.0%). Raloxifene significantly decreased serum calcium and increased iPTH. Our results suggested that raloxifene improved trabecular BMD in postmenopausal Japanese women on hemodialysis. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption. Vitamin D and/or calcium salts should be added to raloxifene treatment to avoid secondary hyperparathyroidism.

Gene Regulation of Atrial Natriuretic Peptide A, B, and C Receptors in Rat Glomeruli

Background and Methods: Atrial natriuretic peptide (ANP) has three types of receptor. We investigated the gene regulation of three types of ANP receptors (ANPR-A, B, and C) in rat glomeruli using reverse transcription coupled with competitive polymerase chain reaction (PCR). Results: Competitive PCR revealed that ANPR-C mRNA expression was most abundant (ANPR-C > A >> B) in glomeruli from control rats among mRNA expressions of three receptors, which were 20- to 15,000-fold higher than those in inner medullary collecting ducts. Two days’ dehydration caused reversible decreases of ANPR-A, B, and C mRNAs by 50–80%. To determine the mechanisms of down-regulation of mRNA expression, isolated glomeruli were incubated in isotonic or hypertonic solution. Hyperosmolality induced by NaCl, mannitol or raffinose caused significant increases of ANPR-A, B, and C mRNA expression. Hypertonicity by urea showed smaller effects. ANP stimulated the expression of ANPR-A, B, and C mRNA in vitro. Conclusion: These results indicate that dehydration caused reversible decreases of ANPR-A, B, and C mRNA expression in glomeruli, and these decreases were not caused by increased plasma osmolality but probably by lower circulating levels of ANP.

Efficacy of Percutaneous Ethanol Injection Therapy for Secondary Hyperparathyroidism in Patients on Hemodialysis as Evaluated by Parathyroid Hormone Levels According to K/DOQI Guidelines

Abstract:  Secondary hyperparathyroidism (SHPT) is a major complication of hemodialysis patients. Recently, percutaneous ethanol injection therapy (PEIT) has become a useful alternative treatment to parathyroidectomy (PTx). In this study, we evaluate the usefulness of PEIT for SHPT according to Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. We studied 28 patients on hemodialysis with high intact‐PTH (>400 pg/mL) and one to four swollen parathyroid glands detected by power Doppler ultrasonography. They were classified into Group 1 (N = 16), with 1 or 2 swollen glands, Group 2 (N = 5), with 3 or 4 swollen glands, and Group 3 (N = 7), high‐risk patients for PTx. We compared serum intact‐PTH levels 1 year after PEIT according to K/DOQI guidelines among these groups. We also evaluated the effectiveness of PEIT and PTx by comparing intact‐PTH levels in 21 patients 1 year after PEIT (groups 1 and 2) with 11 patients after PTx. In Group 1, adequate intact‐PTH levels were noted in 13 of 16 (81.2%) patients after PEIT, while 1 patient of 5 (20%) was achieved in Group 2, and 2 of 7 (28.6%) patients of Group 3. Adequate intact‐PTH levels were attained in 14 of 21 (66.7%) patients of the PEIT group but only in 2 of 11 (18.2%) patients of the PTx group. Our results suggest that PEIT is a useful treatment for SHPT, especially in patients with one or two swollen glands. Through appropriate selection of patients for PEIT and correct injection of ethanol into the enlarged parathyroid gland, PEIT could accomplish better outcomes based on K/DOQI guidelines.

Comparison of Sevelamer Hydrochloride With Colestimide, Administered Alone or in Combination With Calcium Carbonate, in Patients on Hemodialysis

Abstract:  Since hyperphosphatemia in hemodialysis patients can cause secondary hyperparathyroidism and promotes vascular calcification, serum phosphate (Pi) levels must be controlled by phosphate binders. Although sevelamer and colestimide are known as similar non‐calcium, non‐aluminum phosphate binders in hemodialysis patients, there are no studies that compare the effects of the two agents as either a monotherapy or in combination with calcium carbonate (CaCO3). We randomly allocated 62 hemodialysis patients with hyperphosphatemia to treatment with sevelamer (3.0 g/day) and colestimide (3.0 g/day). During the study, 35 subjects dropped out, leaving 13 in the sevelamer group and 14 in the colestimide group. After a 2‐week CaCO3 washout, all subjects received the monotherapy for 4 weeks and then CaCO3 (3.0 g/day) was added for another 4 weeks. Serum corrected calcium levels tended to decrease in both groups during the washout period and monotherapy, but there was no significant difference between the two groups after the addition of CaCO3. Although the calcium × phosphorus product (Ca × P) in the two groups increased during the washout period, there was no significant change or difference between the two groups during monotherapy. However, the addition of CaCO3 significantly reduced serum Pi at Week 8 compared to that at Week 0 in both groups, and significantly lowered Ca × P only in the sevelamer group, but not in the colestimide group. In this short‐term study, sevelamer and colestimide similarly ameliorated hyperphosphatemia, but the combination of sevelamer and CaCO3 was more effective than colestimide with CaCO3 in controlling the Ca × P product, and it may improve cardiovascular mortality in hemodialysis patients.

Parathyroidectomy markedly reduces oxidative stress in a patient with primary hyperparathyroidism.

Parathyroidectomy for hyperparathyroidism has been associated with a survival benefit, but the mechanisms remain unclear. We are reporting on an 88‐year‐old female patient who had high serum calcium and intact parathyroid hormone levels associated with an enlarged parathyroid gland. A parathyroidectomy was performed due to a diagnosis of primary hyperparathyroidism. After the surgery, there was a marked decrease in the oxidative stress markers, such as the ratios of oxidized to unoxidized albumin and advanced oxidation protein products. These results suggest that parathyroidectomy reduces oxidative stress in patients with primary hyperparathyroidism, which may in part explain the reduced risk for cardiovascular and all‐cause mortality after parathyroidectomy.

The whole-PTH/intact-PTH ratio is a useful predictor of severity of secondary hyperparathyroidism.

Background. The newer parathyroid hormone (PTH) assay, whole-PTH, uses an antibody that binds the region harbouring the first amino acid, making it specific for the complete molecule, 1–84-PTH. Especially among dialysis patients, it has been reported that the level of whole-PTH can be calculated as ∼60% of their intact-PTH value. In addition, since 1–84-PTH is part of intact-PTH, the whole-PTH/intact-PTH ratio should not theoretically exceed 1. However, an abnormally high 1–84-PTH/intact-PTH ratio is reported in a few patients with parathyroid carcinoma, primary hyperparathyroidism and secondary hyperparathyroidism. In this study, we examined the correlation between the 1–84-PTH/intact-PTH ratio and the severity of hyperparathyroidism in patients on haemodialysis (HD). Patients and methods. The study population comprised 196 HD patients (males 113, females 83, age 67.4 ± 13.6 years, HD period 8.1 ± 7.3 years; mean ± SD). The whole-PTH/intact-PTH ratio was compared in patients with high PTH levels (intact-PTH ≥300 pg/ ml; high PTH group, n = 32), moderate PTH levels (intact-PTH >150–<300 pg/ml; moderate PTH group, n = 50) and low PTH levels (intact-PTH <150 pg/ml; low PTH group, n = 114). The ratio was also compared in 25 patients with at least one enlarged gland >0.5 cm3 suggesting nodular hyperplasia, as determined by power Doppler ultrasonography (hyperplasia group) with seven patients without enlarged gland (non-hyperplasia group) and six patients who had undergone total parathyroidectomy (post-PTx group). Results. The whole-PTH/intact-PTH ratio of the high PTH group (0.68 ± 0.1) was significantly higher than those of the moderate (0.61 ± 0.1, P < 0.001) and low (0.52 ± 0.1, P < 0.001) groups. Moreover, the ratio was significantly higher in the hyperplasia group (0.70 ± 0.1) than those in the non-hyperplasia group (0.59 ± 0.1, P < 0.05) and post-PTx group (0.456 ± 0.12, P < 0.001). Conclusions. The whole-PTH/intact-PTH ratio correlated with the severity of hyperparathyroidism. Our results suggest that the ratio might be a useful predictor of severity of secondary hyperparathyroidism in HD patients.

Clinical Usefulness of a New Hepatitis C Virus RNA Extraction Method Using Specific Capture Probe and Magnetic Particle in Hemodialysis Patients

Abstract:  Hemodialysis patients are a high‐risk group for hepatitis C virus (HCV) infection. Assessment of HCV infection using HCV‐RNA assay among dialysis patients is important for the issue of safety and environmental protection. However, polymerase chain reaction (PCR)‐based methods are unsuitable for analyzing samples from dialysis patients because the conventional centrifugal extraction method fails to eliminate heparin, a potent inhibitor of PCR. In this study, we evaluated the usefulness of a HCV‐RNA extraction method using probes and magnetic particles for hemodialysis patients in comparison with the centrifugal method. The study population consisted of 17 HCV antibody‐positive patients undergoing hemodialysis. These 17 patients consisted of 12 HCV carrier patients and five patients with past HCV infection. One hundred and two samples from these patients were measured using the centrifugal and magnetic methods. Moreover, we prepared five standards that included theoretically 5 KIU/mL of HCV. One was made from non‐HD patients serum and the other four were from hemodialysis patients’ serum. These standards were measured using the two methods. False‐negative results were not observed with the magnetic method, but were observed in five out of 102 samples with the centrifugal method. Studies using standard samples revealed that accurate HCV‐RNA measurement is achieved using the magnetic method. In conclusion, the present study showed that this magnetic extraction method is a highly reproducible and reliable assay to obtain correct information about the presence of the infective virus itself in the hemodialysis setting. Precise identification of HCV‐RNA using this specific method is considered to be useful in preventing HCV infection in hemodialysis units.

Effect of a Ferric Citrate Formulation, a Phosphate Binder, on Oxidative Stress in Chronic Kidney Diseases-Mineral and Bone Disorder Patients Receiving Hemodialysis: A Pilot Study.

A ferric citrate formulation for treating hyperphosphatemia is a new therapeutic that not only suppresses the accumulation of phosphorus in patients with chronic kidney disease-mineral bone disorders (CKD-MBD), but also ameliorates anemia caused by iron deficiency. In contrast, it has been demonstrated that intravenous iron injection markedly increases oxidative stress. This study was designed to investigate the effect of a ferric citrate formulation on oxidative stress in CKD-MBD patients receiving hemodialysis therapy. Fifteen CKD-MBD patients undergoing dialysis were enrolled in this study. The patients were orally administered a ferric citrate formulation for 6 months. Their plasma phosphorus concentrations remained unchanged with the switch from other phosphorus adsorbents to the ferric citrate formulation. In addition, the ferric citrate formulation generally allowed for dose reduction of an erythropoiesis stimulating agent with an increased hematopoietic effect. The average values of plasma ferritin level increased after the introduction of a ferric citrate formulation, but did not exceed 100 (ng/mL). Interestingly, oxidative stress markers did not increase significantly, and anti-oxidative capacity was not significantly decreased at 6 months after the drug administration. Similarly, no change was observed in any inflammation markers. The ferric citrate formulation induces negligible oxidative stress in CKD-MBD patients receiving dialysis under the present clinical condition.