Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients.

BACKGROUND: Cinacalcet hydrochloride (KRN1493) acts on the parathyroid calcium receptors to suppress parathyroid hormone (PTH) secretion, and is already in wide use in the United States and the European countries. In this study, we examined the efficacy and safety of cinacalcet in Japanese patients on maintenance haemodialysis. METHODS: One hundred forty-four patients with serum intact PTH (iPTH) levels >or=300 pg/ml were enrolled and randomly allocated to two groups assigned to receive either cinacalcet or placebo for 14 weeks. Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target iPTH level of <250 pg/ml. RESULTS: Cinacalcet significantly decreased the median iPTH level from 606.5 pg/ml to 241.0 pg/ml, despite the mean dialysis vintage being 2.4 times longer (14.3+/-7.1 years) and the proportion of patients receiving vitamin D sterols being higher, than in the phase 3 studies conducted in the US/EU. The target iPTH level was achieved in 51.4% of the patients in the cinacalcet group, in sharp contrast to only 2.8% in the placebo group. Furthermore, the percentage of patients with both the serum calcium and phosphorus levels within the target range in the K/DOQI guidelines increased from 4.2% to 26.4% by cinacalcet. CONCLUSIONS: These results suggest that lower dose levels of cinacalcet, as compared to those in US/EU studies, may be sufficient effectively suppress the serum iPTH levels and allow favourable management of the serum calcium and phosphorus levels in Japanese patients, having a longer average dialysis vintage.

Efficacy of percutaneous ethanol injection therapy (PEIT) is related to the number of parathyroid glands in haemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: Percutaneous ethanol injection therapy (PEIT) is used for advanced secondary hyperparathyroidism. We investigated the efficacy, remission period and risk of relapse to determine the effect of the number of hyperplastic glands and other factors on the therapeutic effect of PEIT. METHODS: We studied 321 patients divided into two groups: effective [serum corrected calcium (cCa) level < or =10.5 mg/dl and serum intact parathyroid hormone (iPTH) level < or =250 pg/ml], and ineffective (failed to achieve the target levels). Advanced hyperplasia was defined as an estimated volume > or =0.5 cm(3) on ultrasonography. RESULTS: PEIT was effective in 201 patients (62.6%), in whom serum iPTH levels dropped from 603+/-292 to 183+/-62 pg/ml (ng/l) and serum cCa levels from 10.7+/-0.8 to 10.1+/-0.5 mg/dl. Univariate analysis identified age, the number of hyperplastic glands and iPTH level as factors related to the efficacy of PEIT. The odds ratio for success vs failure by multivariate analysis was 0.55 times for the number of hyperplastic glands > or =0.5 cm(3) (> or =2 vs 0,1) and 0.29 times for iPTH (> or =500 vs <500 pg/ml). Using the Kaplan-Meier method, the number of hyperplastic glands > or =0.5 cm(3) (> or =2 vs 0,1) was a factor affecting the remission period, with a remission significantly longer seen in the group with one hyperplastic gland (P=0.0025). CONCLUSIONS: Superior results in efficacy rate, remission period and risk of relapse are obtained when PEIT is restricted to patients with one hyperplastic gland > or =0.5 cm(3).

Impact of sevelamer hydrochloride and the K/DOQI guidelines.

Sevelamer hydrochloride (SH) was registered as a new drug under the Japanese national health insurance scheme in 2003, and the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for the treatment of renal osteodystrophy were released the same year. At that time, treatment objectives for hemodialysis outpatients at the Kojinkai Ishimaki Clinic were settled established and the outcomes reviewed 18 months later. The relationship between the type and dosage of phosphate binder (PB), and the concentrations of adjusted calcium (Ca), phosphorus (P), intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) was examined. Patients receiving calcitriol or maxacalcitol intravenous pulse therapy, or who had undergone simultaneous pancreas-kidney transplant, were excluded from this analysis. The PB was CaCO3 in 60% of cases, SH in 33.3%, and a combination of both in 21.9%; no PB was used in 6.7% of cases. The dosage of CaCO3 was 2.8+/-1.0 g/day, and 1alpha-hydroxy activated vitamin D3 (VD) was 0.46+/-0.24 microg/day; the respective concentrations of adjusted Ca, P, intact PTH, and BAP were 9.4+/-0.7 mg/dL, 5.6+/-1.7 mg/dL, 104+/-83.9 pg/mL, and 22.7+/-10.9 IU/L. In the SH monotherapy group, the dosage of SH was 3.9+/-0.725 g/day, and VD 0.62+/-0.21 microg/day, and the concentrations for adjusted Ca, P, intact PTH, and BAP were 9.6+/-0.4 mg/dL, 6.2+/-1.5 mg/dL, 150+/-42.9 pg/mL, and 38.5+/-14.2 IU/L, respectively. In the combined therapy group, the dosage of CaCO3 was 2.9+/-0.9 g/day, SH was 3.3+/-1.1 g/day, VD was 0.53+/-0.27 microg/day, and the respective concentrations were 9.2+/-1.0 mg/dL, 5.7+/-1.4 mg/dL, 160+/-107.8 pg/mL, and 31.3+/-42.0 IU/L. One-third of all subjects were administered SH, either as monotherapy or in combination with CaCO3, and in these patients the dosage of VD was able to increase.

[Front line of management of hyperphosphatemia in hemodialysis patients].

Management of hyperphosphatemia in hemodialysis patients is very important to prevent progress of renal hyperparathyroidism or ectopic calcification. Sevelamer hydrochloride is a Ca and Al free phosphate binder, and reduces serum phosphorus level, without any influence on serum Ca level, and Ca-P products. This compound is expected to reduce the incidence of arterial calcification, and improve the QOL (quality of life) of hemodialysis patients.

[Advantage of intravenous pulse therapy with calcitriol or maxacalcitol in dialysis patients with renal hyperparathyroidism].

In dialysis patients, deficiency of calcitriol down regulates vitamin D receptor (VDR) and decreases density of Ca sensing receptor, resulting right shift of set point of extra cellular Ca concentrations to release of parathyroid hormone. And then, renal hyperparathyroidism occurs and progresses. The purpose of pulse therapy with calcitriol or its analogue is elevating extra cellular calcitriol level up to supra physiological level, which up regulates VDR and shift the set point to left. The extra cellular calcitriol level after injection of calcitriol cannot compare with the level after oral administration of calcitriol at the same dose. The left shift of set point is investigated 4 weeks after intravenous pulse therapy with calcitriol or maxacalcitol, and degree of shift to the left depends on the single dose of these medicines. There is another advantage of intravenous pulse therapy, which takes no account of drug compliance or existence of malabsorption of lipid soluble vitamins.

The effects of physical activity and autonomic nerve tone on the daily fluctuation of blood pressure.

The effects of daily activity and autonomic nerve tone on the fluctuation of ambulatory blood pressure were studied in hypertensive patients. The autonomic nerve tone was measured by frequency domain analysis of the RR interval. Physical activity was evaluated by a walk count, converted to a walk rate (WR), recorded using a digital Holter ECG fitted with an accelerometer, with simultaneous monitoring of blood pressure (Bp). Average values of the WR, H and L/H components were calculated for the 15 min. period just prior to Bp monitoring. The relationship between the average WR, H and L/H values and the Bp was determined by a linear regression analysis. Hypertension was classified into three types, autonomic nerve dominant (AN), exercise dominant (EX), and irregular (IR), based on a high correlation coefficient between Bp and either H or L/H (AN type), between Bp and WR (EX type), or no significant correlation between Bp and any of the parameters (IR type). Of the thirty hypertensive patients studied 11 were classified as AN, 12 as EX, and 7 as IR. Patients of the EX type had significantly lower Bp than patients in the other two classes. Furthermore, all of the IR type patients showed non-dipper type hypertension, suggesting that the Bp regulation mechanisms were impaired. The results suggest the significance of simultaneous monitoring of physical activity and autonomic nerve function at the time of Bp monitoring.

Guidelines for percutaneous ethanol injection therapy of the parathyroid glands in chronic dialysis patients.

Percutaneous ethanol injection therapy (PEIT) of the parathyroid was originally introduced as an alternative to surgical parathyroidectomy. After the recent elucidation of the pathogenesis of parathyroid hyperplasia in uraemia, 'selective PEIT of the parathyroid glands' was developed, in which enlarged parathyroid glands with nodular hyperplasia are 'selectively' destroyed by ethanol injection, and other glands with diffuse hyperplasia are then managed by medical therapy. The 'Guidelines for percutaneous ethanol injection therapy of the parathyroid glands in chronic dialysis patients' proposed by the Japanese Society for Parathyroid Intervention are presented, including indications, techniques, and post-PEIT management. These guidelines also apply to direct injection therapy using drugs other than ethanol, such as calcitriol and 22-oxacalcitriol.

Intervention for recurrent secondary hyperparathyroidism from a residual parathyroid gland.

There is a significant recurrence rate of secondary (renal) hyperparathyroidism after total parathyroidectomy (PTx) with forearm autograft. The lesions responsible for recurrent hyperparathyroidism are mainly the parathyroid autografts, but in some cases there are previously undetected residual or ectopic parathyroid glands. In Kojinkai hospitals, 155 haemodialysis out-patients had total PTx and forearm autograft for severe renal hyperparathyroidism and, during the past 18 years, 40 of them developed recurrent or persistent renal hyperparathyroidism. Five patients were treated by percutaneous ethanol injection therapy (PEIT): four patients had residual parathyroid glands and one patient had an ectopic parathyroid gland. The results of PEIT depended on the functioning of the parathyroid autografts. In two patients with non-functioning autografts, the effect of PEIT was remarkable; both showed 'hungry bone' syndrome and became hypoparathyroid. In the three patients with functioning autografts, the clinical course after PEIT was mild, but resection of the autograft was required in one patient. When an echo-guided approach is possible, PEIT for residual parathyroid glands is an effective intervention for the management of recurrent renal hyperparathyroidism; however, there is a risk of hypoparathyroidism in patients with non-functioning parathyroid autografts. As parathyroid autografts consist of multiple nodules, echo-guided injection of ethanol or calcitriol to each nodule is almost impossible and therefore resection of the autograft is indicated for autograft-dependent recurrent renal hyperparathyroidism.