Darbepoetin alfa effectively maintains hemoglobin concentrations at extended dose intervals relative to intravenous rHuEPO in Japanese dialysis patients.

Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its three-fold longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. In this multicenter, open-label study, 513 dialysis patients maintained on stable rHuEPO therapy were switched to KRN321 at extended dose intervals. Those receiving rHuEPO two (n = 144, 28.1%) or three times (n = 305, 59.5%) per week were switched to KRN321 once per week, and those receiving rHuEPO once per week (n = 64, 12.5%) were switched to KRN321 once every two weeks. The doses of KRN321 (10-120 microg) were titrated to maintain Hb concentrations at 10-13 g/dL and, if possible, within 11-12 g/dL for up to 52 weeks. If the Hb concentration remained between 10.5 and 12 g/dL, conversion of the dosing frequency from once per week to once every two weeks was allowed. Hemoglobin concentrations were maintained regardless of the dosing interval. The percentage of patients with Hb values within 11-12 g/dL was 23.6% at week 0, 41.3% at week 7, 46.1%-51.9% between weeks 11 and 22 and 45.6% at week 52. KRN321 was well tolerated and the safety profile was consistent with previous trials conducted for KRN321. KRN321, when administered at extended dose intervals, is well tolerated and effective Hb concentrations are attained in Japanese hemodialysis patients.

Prognostic factors for a composite end-point of renal outcomes in patients with chronic kidney disease.

We aimed to investigate prognostic factors for a composite end-point of end-stage renal disease (ESRD) and the progression of renal disease in Japanese patients with chronic renal disease. Using a composite end-point comprising a doubling of serum creatinine (sCr), an increase in sCr level to 6.0 mg/dL, or initiation of dialysis and renal transplantation caused by ESRD, we examined data obtained in a prospective cohort study. The present study consisted of 641 patients who were 20 years of age or older with chronic renal disease caused by diabetic nephropathy, glomerulonephritis, or nephrosclerosis, and who had baseline sCr levels of 5.0 mg/dL or less. The following criteria were examined as prognostic factors: sex; age; elapsed time from initial diagnosis; disease underlying the nephropathy (diabetic or non-diabetic); complications with hypertension, hyperlipidemia, or anemia; baseline sCr level; therapeutic regimen, including use of ACE inhibitors or Ca2+ -channel blockers; and diet. A log-rank test was used for univariate analysis, and Cox regression analysis was used for multivariate analysis. Underlying disease (diabetic or non-diabetic), baseline sCr level, and Ca2+ -channel blocker therapy were significantly related to event incidence. In the present study, we identified underlying disease and baseline sCr level as important prognostic factors for a composite end-point in a predialysis patient population in both the early and middle stages of renal disease. These factors should be considered as balancing variables for randomization in future clinical studies.

Effect of combined treatment of oral sorbent with protein-restricted diet on change of reciprocal creatinine slope in patients with CRF.

BACKGROUND: Low-protein diet (LPD) is one therapy and AST-120, an oral carbon adsorbent, is the other therapy to reduce blood levels of indoxyl sulfate in patients with chronic renal failure (CRF). Based on the different mechanisms of reducing indoxyl sulfate levels, the addition of AST-120 to an LPD was investigated. METHODS: Seven hundred twenty-two patients with chronic glomerulonephritis (CGN) and 162 patients with diabetic nephropathy (DN) were stratified by protein intake: less than 0.50 g/kg/d (0.50-g/kg/d group), 0.51 to 0.65 g/kg/d (0.65-g/kg/d group), and 0.66 to 0.80 g/kg/d (0.80-g/kg/d group). To analyze the effect of combined AST-120 therapy (6 g/d) in patients on LPD therapy, the slope of the reciprocal of serum creatinine (1/Cr slope), which represents progression of CRF, was applied. RESULTS: (1) In patients with CGN, the addition of AST-120 with an LPD was as follows: the 1/Cr slope in the 0.50-g/kg/d (n = 152), 0.65-g/kg/d (n = 318), and 0.80-g/kg/d (n = 252) groups changed significantly from -430 x 10(-5) to -83 x 10(-5), -333 x 10(-5) to -102 x 10(-5), and -431 x 10(-5) to -116 x 10(-5) dL/mg/wk. (2) In patients with DN, the addition of AST-120 with an LPD was as follows: the 1/Cr slope in the 0.65-g/kg/d (n = 74) and 0.80-g/kg/d (n = 68) groups changed significantly from -602 x 10(-5) to -125 x 10(-5) and -646 x 10(-5) to -185 x 10(-5) dL/mg/wk. CONCLUSION: It is suggested that the addition of AST-120 to a mild LPD provides the comparable effect with a strict LPD in the point of suppressing the progress of CRF.

Clinical effect of short daily in-center hemodialysis.

BACKGROUND: The safety and efficacy of short daily hemodialysis has been reported in the USA and Europe, but there is no report on its efficacy in Japanese patients undergoing hemodialysis. METHODS: Twenty-three outpatients (14 men and 9 women, 55.8 +/- 9.6 years old and 11.1 +/- 6.6 years on dialysis) undergoing hemodialysis 3 times/week participated in this study. After 4 weeks' baseline observation under conventional hemodialysis, they were subjected to short daily in-center hemodialysis (DHD, 6 times/week) for 12 weeks and then a 4-week follow-up observation period under conventional hemodialysis. RESULTS: The mean pre-dialysis systolic and diastolic blood pressure significantly decreased in the DHD period. Antihypertensive drugs could be discontinued or the dose was reduced in 6 of 11 patients treated with such drugs. The hematocrit level tended to increase in the DHD period, and recombinant human erythropoietin could be discontinued or reduced in 7 of 14 patients. Localized skin rash caused by the adhesive tape and lidocaine patch at the blood access was observed in only 2 patients, but no other adverse events associated with DHD were noted. CONCLUSION: These results indicate that DHD is safe and more useful than conventional 3 times/week hemodialysis for Japanese patients undergoing hemodialysis.

Clinical analysis of renoprotective responding patients administrated with oral adsorbent in chronic renal failure secondary to chronic glomerulonephritis.

UNLABELLED: An oral adsorbent (AST-120) that removes uremic toxin has attenuated the progression of renal dysfunction. Although there were decreased serum creatinine (Scr) levels observed during administration, it is expected that the action of an oral adsorbent is different according to the patient. In the present study, the difference in the background was clarified. METHODS: A total of 842 patients whose Scr had increased from 3.8 to 4.8 mg/dL during the prior 5.2 months were investigated. Antihypertensive medications and dietary protein intake were unmodified during 6 months administration. The patients were divided into three efficacy groups based on the changes in Scr level: those who had a decrease in Scr were grouped as Group A (N = 290), while those with a < 1.5-fold increase were defined as Group B (N = 428) and those with a > or = 1.5-fold increase were defined as Group C (N = 124). RESULTS: Before administration, these three groups were indistinguishable by the Scr level. No Group A patient went onto dialysis, whereas 12% and 40% of Group B and C patients, respectively, required dialysis. In Group A, the slopes of 1/Scr over time, serum urea nitrogen, uric acid, phosphate, total protein, and diastolic blood pressure were all improved. Group B improved moderately and Group C showed less improvement. CONCLUSIONS: In this study, a fairly large number of patients (29% of the population) were believed to be the first case to report the reversibility of severe chronic renal failure. Except in patients with hypoproteinemia, hypercholesterolemia, anemia or hypertension, AST-120 either attenuates or arrests the progression in patients with severe chronic glomerulonephritis.

Protective effect of an oral adsorbent on renal function in chronic renal failure: determinants of its efficacy in diabetic nephropathy.

Large-scale clinical trials have shown that the oral adsorbent AST-120 improves renal function and delays the initiation of dialysis in chronic renal failure (CRF) secondary to chronic glomerulonephritis. If renal failure progresses via common mechanisms, then the same effects can be expected in diabetic nephropathy. However, no study on diabetic nephropathy has been reported. Thus, we enrolled patients with statistically significant progression of CRF secondary to diabetic nephropathy, and analyzed the changes in renal function after AST-120 therapy, and the clinical factors associated with response to therapy. We enrolled 276 patients with diabetic nephropathy, whose serum creatinine (Scr) had increased from 3.4 to 4.5 mg/dL during the 4.5 +/- 3.7 months prior to the study. These patients took AST-120 at a dose of 5.0 +/- 1.4 g/day for 6 months. The clinical data were analyzed by dividing the patients into three groups based on the changes in Scr after AST-120 therapy, with responders showing a decrease (N = 82), partial responders showing <1.5-fold increase (N = 144), and non-responders showing >/=1.5-fold increase (N = 50). AST-120 significantly lowered the slope of 1/Scr-time line, suggesting that AST-120 suppressed the progression of renal impairment. No responders required dialysis, whereas 24.3% of the partial responders and 36.0% of the non-responders started dialysis therapy. In responders, the 1/Scr-time slope showed a negative-to-positive shift and serum urea nitrogen decreased significantly, whereas the improvement was moderate in partial responders and minimal in non-responders. Among responders, AST-120 therapy significantly improved renal function despite the presence of hypoproteinemia, hyperlipidemia, anemia or hypertension in many patients. The beneficial effect of AST-120 was significantly more marked in patients with blood pressure controlled within the normal ranges and hematocrit maintained at 30% or above. AST-120 reversed renal dysfunction or delayed the initiation of dialysis therapy in patients with progressive aggravation of CRF secondary to diabetic nephropathy, independent of hypoproteinemia, hyperlipidemia, anemia and hypertension. Active use of AST-120 may be recommended in patients with good control of blood pressure and hematocrit above 30%.

Clinical study of cinacalcet in Japan.

For the approval of cinacalcet hydrochloride, five clinical trials have been performed excluding pharmacokinetic studies for healthy volunteers and hemodialysis patients. An early phase II dose-finding study was started for regular hemodialysis patients with secondary hyperparathyroidism from a daily dose of 12.5 mg cinacalcet and increasing 25 mg up to 50 mg for 9 weeks. A placebo-controlled double-blind three dose-finding study (late phase II study) was then conducted. By this trial, an adequate initial dose of cinacalcet was determined as 25 mg daily, and the placebo-controlled double-blind study (phase III study) was started using this initial dose. Two long-term (1 year) phase III open trials were also conducted during and after these phase II and III studies. The results of two double-blind trials (phase II and phase III) and safety profiles of cinacalcet in all Japanese clinical trials for approval are summarized in this article.

Quality of life improvements in dialysis patients receiving darbepoetin alfa.

Short-acting hematopoietic agents can improve the quality of life (QOL) of hemodialysis patients, but questions remain regarding the domains of QOL affected, the relative importance of initial and final hemoglobin (Hb) concentrations, and the use of long-acting hematopoietic agents. We measured Hb concentrations and QOL in 487 hemodialysis patients who were switched from treatment with recombinant human erythropoietin to treatment with darbepoetin alfa. QOL was measured with the Japanese-language version of the SF-36, at the start of therapy with darbepoetin alfa and again 7-14 weeks later. We examined changes in QOL over time in the group as a whole, and in subgroups stratified by the change in Hb concentration. We also studied relationships between the final Hb concentration achieved and the magnitude of change in QOL. QOL scores increased significantly in all SF-36 domains except Social Functioning. The greatest increases were in vitality and in the two role-functioning domains. The magnitude of the increase in Hb concentration was related to the magnitude of the increase in QOL for only one subscale: Vitality. Patients with higher final Hb concentrations also had greater increases in Vitality scores. Hematopoiesis induced by darbepoetin alfa is associated with increased vitality and may also be associated with improved role functioning. Vitality increased significantly only in those patients with the greatest increases in Hb concentration and in those with higher final Hb concentrations.

Darbepoetin alfa (KRN321) administered intravenously once monthly maintains hemoglobin levels in peritoneal dialysis patients.

Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. This multicenter, open-label, single-arm study of 72 patients with end stage renal failure on peritoneal dialysis (PD) evaluated the efficacy and safety of KRN321 administered intravenously with the dosing intervals extended to monthly. PD patients that were either rHuEPO-naïve or rHuEPO-receiving were enrolled. In rHuEPO-naïve patients, the initial dose of KRN321 was 40 mug weekly by intravenous administration. For rHuEPO-receiving patients, an initial regimen of fortnightly intravenous administration was given and the initial dose was based on the dose of rHuEPO used before switching to KRN321. After starting the study medication, the Hb concentration was maintained between 10.0 g/dL and 13.0 g/dL. In those patients whose Hb concentrations showed a stable time-course, the dosing intervals of KRN321 were extended. The results suggest that it may be feasible to reduce the frequency of treatment to a monthly schedule, with an associated adjustment of dose, in most patients. Adverse events were observed in 67 of the 72 patients (93.1%, 267 events). Most of all the adverse events were reported in patients with chronic renal failure receiving conventional rHuEPO. No safety problems specific to KRN321 were noted. These results suggest that KRN321 could reduce of frequency of hospital visits for PD patients receiving erythropoietic therapy for renal anemia.

Dose determination of cinacalcet hydrochloride in Japanese hemodialysis patients with secondary hyperparathyroidism.

Cinacalcet hydrochloride is a calcimimetic agent that activates the calcium-sensing receptor on the surface of parathyroid cells and inhibits parathyroid hormone (PTH) secretion. To manage secondary hyperparathyroidism, cinacalcet, which lowers PTH levels without increasing serum calcium, phosphorus and calcium-phosphorus product (Ca x P) levels, may provide a new potential therapy. To identify the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism, this double-blind, placebo-controlled, parallel, dose-finding study was conducted. One hundred and twenty Japanese hemodialysis patients with intact PTH levels greater than or equal to 300 pg/mL were randomized into four groups: placebo, and 12.5, 25 and 50 mg of cinacalcet. The treatment period was three weeks followed by a two-week follow-up observation period. Cinacalcet decreased serum intact PTH levels in a dose-dependent manner, and also decreased serum calcium, phosphorus, Ca x P, tartrate-resistant acid phosphatase and osteocalcin levels. The treatment with cinacalcet was generally well tolerated in this study. However, the incidence of treatment-related adverse events, such as gastrointestinal disorders and hypocalcemia, and the rate of withdrawal from the study due to treatment-related adverse events were higher in the 50 mg dose group than in the other groups. On the basis of both efficacy and safety results, 25 mg has been identified as the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism.

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.

Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells.

Calcimimetic compounds inhibit not only parathyroid hormone (PTH) synthesis and secretion, but also parathyroid cell proliferation. The aim of this investigation is to examine the effect of the calcimimetic compound NPS R-568 (R-568) on parathyroid cell death in uremic rats. Hyperplastic parathyroid glands were obtained from uremic rats (subtotal nephrectomy and high-phosphorus diet), and incubated in the media only or the media which contained high concentration of R-568 (10(-4)M), or 10% cyclodextrin, for 6h. R-568 treatment significantly suppressed medium PTH concentration compared with that of the other two groups. R-568 treatment not only increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay-positive cells, but also induced the morphologic changes of cell death determined by light or electron microscopy. These results suggest that CaR activation by R-568 accelerates parathyroid cell death, probably through an apoptotic mechanism in uremic rats in vitro.

Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration.

AIMS: To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: Data were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available. The data were analysed by nonlinear mixed effect modelling using NONMEM with a model including endogenous erythropoietin production. In addition, the final model was evaluated using bootstrap resampling. RESULTS: The selected basic model was a two-compartment model with a combination of additive and the constant coefficient of variation error models. The significant covariates were weight (WT) for clearance (CL) and the volume of central compartment (V(1)), and the dialysis technique (DIA) for V(1). The typical values of CL and V(1) were 0.0807 l h(-1) and 2.51 l, respectively. V(1) in PD patients was 17% higher than in HD patients. With the introduction of WT in CL and WT and DIA in V(1), interindividual variability decreased from 27.1% to 20.6% in CL and from 29.1% to 21.8% in V(1). The mean parameter estimates from the bootstrap datasets were similar to those from the original dataset. Evaluation by bootstrapping showed that the final model was stable. CONCLUSIONS: The results of the present analysis suggest no dosage regimen change is warranted for darbepoetin alfa in HD and PD patients over the range of distribution of covariates included in this study.

Up-regulation of Cbfa1 and Pit-1 in calcified artery of uraemic rats with severe hyperphosphataemia and secondary hyperparathyroidism.

BACKGROUND: Cardiovascular disease is the most frequent cause of death in patients with end-stage kidney disease (ESKD). Vascular calcification is a confirmed risk factor for cardiovascular events in the general population and has a high occurrence in patients with ESKD. Despite the high prevalence of vascular calcification in ESKD, the pathogenesis of the disorder is still obscure. The present study examined the expressions of bone-associated factors in calcified arteries in subtotally nephrectomized rats with severe secondary hyperparathyroidism (SHPT). METHODS: Seven-week-old male Sprague-Dawley rats were divided into five groups as follows: sham-operated rats that received a normal diet [0.8% of phosphorus (P), 1.1% of calcium (Ca)] (Sham), sham-operated rats that received a high-phosphorus and low-calcium (HPLCa) diet (1.2% P, 0.4% Ca) (Sham+HPLCa), 5/6 nephrectomized rats that received a normal diet as the uraemic control group (Nx), and 5/6 nephrectomized rats that received a HPLCa diet to induce the development of SHPT (Nx+HPLCa), and 5/6 nephrectomized and parathyroidectomized rats that received a HPLCa diet (Nx+PTx+HPLCa). The feeding period of each group was 10 weeks. The rats were then sacrificed and their serum was examined. The upper part of the abdominal aorta was used to investigate the expression of mRNAs of core-binding factor alpha-1 (Cbfa1) and sodium-dependent phosphate cotransporter (Pit-1) by real-time reverse transcriptase polymerase chain reaction (real-time PCR) analysis. The lower part was examined for calcification by von Kossa staining. RESULTS: Serum P level and Ca x P products increased significantly in the Nx+HPLCa group compared with those of any other groups. Severe hyperparathyroidism was also observed in the Nx+HPLCa group. Vascular calcification (medial layer) was observed in the Nx+HPLCa group only. There was a significant increase in Cbfa1 and Pit-1 mRNA expression levels in the aorta of the Nx+HPLCa group compared with that of any other groups. CONCLUSIONS: These results suggest that medial layer vascular calcification in uraemic rats with severe hyperphosphataemia and SHPT may be caused in part by Cbfa1 and Pit-1.

The calcimimetic agent KRN 1493 lowers plasma parathyroid hormone and ionized calcium concentrations in patients with chronic renal failure on haemodialysis both on the day of haemodialysis and on the day without haemodialysis.

AIMS: Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in patients with secondary hyperparathyroidism; however, hypercalcaemia, hyperphosphataemia, or both, often develop. Calcimimetic agents, employed in alternative therapeutic approaches, directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands. METHODS: In this study, patients were given orally 25, 50, and 100 mg doses of the calcimimetic agent KRN 1493 each on two occasions, on the day of haemodialysis and on the day without haemodialysis. RESULTS: In the pharmacokinetic results, because the clearance of KRN 1493 by haemodialysis was much smaller than the systemic clearance, the influence of haemodialysis was not remarkable. In the pharmacodynamic study, on both the days with or without haemodialysis, plasma PTH concentrations decreased in a dose-dependent manner. Serum calcium concentrations decreased in association with the decrease in plasma PTH concentrations. Mild dose-dependent adverse effects (mainly nausea) were seen after the administration of KRN 1493 on both the day of haemodialysis and the day without haemodialysis. CONCLUSIONS: We conclude that the pharmacokinetics of KRN 1493 after a single administration were similar on the day of haemodialysis and the day without haemodialysis. KRN 1493 is safe and effective in suppressing PTH secretion and serum calcium concentrations on the day of haemodialysis and on the day without haemodialysis in patients with secondary hyperparathyroidism.

Clinical effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in hemodialysis patients.

Orthostatic hypotension is one of the major factors interfering with everyday activities in hemodialysis patients, but there has been no effective agent for treating it. In order to clarify the clinical effects of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on orthostatic hypotension of hemodialysis patients, we conducted a randomized, double-blind comparative trial. 149 regular hemodialysis patients with orthostatic hypotension were randomly allocated to three groups and L-DOPS at doses of 400 mg, 200 mg or placebo was orally administrated to each group 30 min before starting every hemodialysis for 4 weeks. Changes of blood pressure (BP) in orthostatic hypotension immediately after completion of hemodialysis and symptoms related to orthostatic hypotension were compared between the three groups. In the 400-mg group, systolic and diastolic BP after standing increased significantly and the drop of mean BP after standing was also reduced compared with pretreatment levels. No such changes were observed in the placebo group. Fatiguability, malaise/weakness, dizziness and light-headed feeling, the interdialytic symptoms commonly observed in hemodialysis patients who developed orthostatic hypotension, were improved to a significant extent in the L-DOPS group compared with the placebo group. In particular, the improvement was more remarkable for the L-DOPS 400-mg group than the placebo group in patients with diabetic nephropathy, lower systolic BP after standing, and the long duration type of orthostatic hypotension. The incidence of adverse events was comparable between the three groups, and all recovered after discontinuation of L-DOPS or concomitantly administered drugs, or without any treatment. These findings indicate that L-DOPS taken before hemodialysis prevents orthostatic hypotension in patients undergoing hemodialysis, and is also effective for the interdialytic symptoms related to orthostatic hypotension.

Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency.

The reduced expression level of the calcium-sensing receptor (CaR) is attributed to the hyposensitivity of parathyroid cells to extracellular calcium concentration [Ca2+]o, which plays a crucial role in the pathogenesis of secondary hyperparathyroidism (SHPT) in patients and rats with chronic renal insufficiency (CRI). Calcimimetic compounds have been demonstrated to improve the decreased sensitivity of CaR to extracellular calcium concentration and to suppress both parathyroid hormone (PTH) oversecretion and parathyroid cell proliferation. However, the effect of calcimimetics on the reduced CaR expression level in parathyroid cells in CRI remains unclarified. The aim of this investigation was to examine the effect of the calcimimetic compound NSP R-568 (R-568) on the CaR expression in the parathyroid cells of rats with experimental CRI. Subtotally nephrectomized rats were fed a high-phosphorus diet for 8 (n = 12; Nx-8 group) or 9 wk (n = 11; Nx-9 group) to induce severe SHPT. Another group of uremic rats were fed a high-phosphorus diet for 8 wk and then orally administered R-568 (100 micromol/kg body wt) once a day for 7 d (n = 11; Nx+R-568 group). Sham-operated rats that were fed a standard diet for 9 wk were used as controls (n = 8). R-568 treatment induced a significant reduction in plasma PTH level with significant decrease in serum calcium and without change in serum phosphorus concentration. Serum 1,25(OH)2D3 level was not affected by R-568 administration. CaR mRNA and protein levels in the Nx-8 and Nx-9 groups significantly decreased compared with those in the controls; however, no significant difference in these parameters was observed between the Nx-8 and Nx-9 groups. In the Nx+R-568 group, CaR mRNA and protein levels significantly increased compared with those in either the Nx-8 or Nx-9 group. R-568 was effective in reducing the number of proliferating cell nuclear antigen-positive cells along with parathyroid gland growth suppression in the Nx+R-568 group compared with that in the Nx-9 group. The results suggest that the calcimimetic compound R-568 upregulates decreased CaR expression, and the upregulation possibly has an enhancement effect on PTH secretion and parathyroid cell hyperplasia through the improved sensitivity of CaR to [Ca2+]o.