Effects of evocalcet on parathyroid calcium-sensing receptor and vitamin D receptor expression in uremic rats.

Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague-Dawley rats fed a high-phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups-baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers.

Fibroblast Growth Factor 23 Exacerbates Cardiac Fibrosis in Deoxycorticosterone Acetate-Salt Mice With Hypertension.

Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease; however, the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model with mild chronic kidney disease and hypertension as well as heart failure with a preserved ejection fraction. Wild-type male mice were randomly allocated to 4 groups: normal control, vehicle-treated DOCA-salt mice, FGF23-treated DOCA-salt mice, and FGF23- and calcitriol-treated DOCA-salt mice. The DOCA-salt mice received the agents via the CIV route for 10 days using an infusion minipump. DOCA-salt mice that received FGF23 showed a marked increase in the serum FGF23 level, and echocardiography in these mice revealed heart failure with a preserved ejection fraction. These mice also showed exacerbation of myocardial fibrosis, concomitant with an inverse and significant correlation with Cyp27b1 expression. Calcitriol treatment attenuated FGF23-induced cardiac fibrosis and improved diastolic function via inhibition of transforming growth factor-ß signaling. This effect was independent of the systemic and local levels of FGF23. These results suggest that CIV FGF23 loading exacerbates cardiac fibrosis and that locally abnormal vitamin D metabolism is involved in this mechanism. Calcitriol attenuates this exacerbation by mediating transforming growth factor-ß signaling independently of the FGF23 levels.

One-Year Romosozumab Treatment Followed by One-Year Denosumab Treatment for Osteoporosis in Patients on Hemodialysis: An Observational Study.

There is limited evidence on the use of romosozumab (ROMO) in the treatment of osteoporosis in patients on hemodialysis (HD); thus, we aimed to investigate this topic. This prospective, observational, single-center cohort study included 13 prior osteoporosis treatment-naïve patients on HD with osteoporosis. They first received ROMO once monthly for 12 months (210 mg; subcutaneously once every month). Thereafter, they received denosumab (DENO) for an additional 12 months (60 mg; subcutaneously once every 6 months). We examined the incidence of new fractures; treatment safety; and temporal changes in the bone mineral density (BMD), bone metabolism markers, and vascular calcification. No new cases of fractures were noted. The median one-year percentage changes (from the baseline) in the BMDs at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were + 9.0%, + 2.5%, and + 4.7%, respectively. These changes were maintained for 24 months. The corresponding relative changes from the baseline to 24 months thereafter were + 14.9%, + 5.4%, and + 6.5%, respectively. The percentage changes in TH BMD and FN BMD were negatively correlated with baseline BMD. Coronary artery and thoracic aorta calcification scores increased slightly from baseline to 12 months thereafter. However, fatal events (cardiovascular disease-associated and all-cause deaths) did not occur during ROMO treatment. Effectiveness of ROMO was better in patients who had severe osteoporosis with low TH BMD, low FN BMD, and high tartrate-resistant acid phosphatase 5b level at ROMO initiation.

Romosozumab successfully regulated progressive osteoporosis in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis.

Osteoporosis is a crucial complication in patients with chronic kidney disease (CKD), similar to that in the general population. Although romosozumab, a monoclonal antibody targeting sclerostin, has been administered for patients with CKD, its clinical effectiveness in these patients, especially in patients on hemodialysis (HD), remains to be studied. Herein, we report the case of a 42-year-old man on HD who developed severe osteoporosis. Serum calcium levels were extremely high, bone metabolic markers were abnormal, and the patient had pathological fractures. The bone biopsy indicated a bone metabolism disorder and high bone turnover. We administered romosozumab once a month as an intervention for bone alteration. Through the 10-month usage, bone metabolic markers improved, and the decrease in bone mineral density was ameliorated. We hypothesized that romosozumab could be a therapeutic option for osteoporosis in patients undergoing HD, especially in those with bone mineralization disorders.

Tumoral calcinosis due to severe hyperphosphatemia and secondary hyperparathyroidism without vascular calcification in a hemodialysis patient.

We report a case of a 32-year-old man who was undergoing chronic hemodialysis and had hyperphosphatemia and secondary hyperparathyroidism (SHPT) with multiple tumoral calcinosis (TC) lesions refractory to drug therapy. Total parathyroidectomy and autotransplantation were performed, and he recovered from TC within 3 months. Several soft-tissue calcifications were present, but neither computed tomography (CT) before diagnosis nor CT performed 12 months after surgery detected evidence of vascular calcification (VC), despite persistence of hyperphosphatemia. This patient had a high calcium (Ca) × phosphate (P) product and calciprotein particles, and high serum Ca and P levels are important risk factors for both TC and VC. P plays a crucial role in regulation of VC, but the absence of VC in our case suggests a specific circumstance in which VC does not progress even under a high phosphatemic state, and that P alone may be insufficient for VC progression. TC in our patient was probably due to severe SHPT and continuous high serum P and Ca × P product levels, but the absence of VC suggests that the pathophysiologic process leading to VC requires further investigation, particularly in chronic kidney disease.

Anti-MDA-5 antibody-positive clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease treated with therapeutic plasma exchange: A case series.

We present six cases of antimelanoma differentiation-associated gene 5 antibody (anti-MDA5-Ab)-positive clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD), which is known to have a poor prognosis. The outcomes of these cases are described after treatment with therapeutic plasma exchange (TPE). Clinical and therapeutic data for patients with CADM with RP-ILD were collected retrospectively from medical records. All six patients received early intensive care including high-dose corticosteroids, intravenous cyclophosphamide, and a calcineurin inhibitor, but lung disease and hypoxia became more severe. TPE was performed over a median of 9.5 sessions (range 3-14) per patient, and the median duration from admission to TPE was 23 days. Three patients received combined direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX-DHP) therapy on successive days to manage acute respiratory failure. Four patients survived and two died due to respiratory failure. In the survival cases, ferritin decreased, and ferritin and KL-6 were lower at diagnosis. The patients who died had a higher alveolar-arterial oxygen difference and more severe lung lesions at the time of initiation of TPE. These findings indicate that a combination of conventional therapy and TPE may be useful for improvement of the prognosis of CADM with RP-ILD at the early stage of onset.

Early response of the parathyroid gland to withdrawal of a calcimimetic compound in uremic rats.

Little is known about changes in parathyroid cells when calcimimetics are withdrawn. We examined the response of parathyroid glands to cinacalcet (Cina) withdrawal in uremic Sprague-Dawley rats fed a high-phosphate diet to develop secondary hyperparathyroidism and divided into groups treated with vehicle (UC), Cina, and Cina and maxacalcitol (Maxa), a vitamin D receptor activator (CiNa + Maxa). After 2 wk of treatment, vehicle and Cina were withdrawn and Maxa was continued. Rats were analyzed immediately (day 0) and 7 days (day 7) after withdrawal. The Cina and CiNa + Maxa groups had significantly lower parathyroid hormone (PTH) than the UC group on day 0, although PTH in the Cina group reached UC levels on day 7. On day 0, there were significantly more proliferating cell nuclear antigen-positive cells in the UC group compared with normal controls, and this increase was significantly suppressed in the Cina and CiNa + Maxa groups. On day 7, the Cina group, but not the CiNa + Maxa group, showed a significant increase in proliferating cell nuclear antigen-positive cells compared with the UC group. This increase was related to parathyroid cell diameter regression to UC levels, whereas combination treatment maintained diameter suppression. These results indicate that parathyroid growth activity is stimulated by Cina withdrawal, although the PTH level was not further increased. Continuous administration of Cina may be required for optimal control of secondary hyperparathyroidism, and simultaneous use of a vitamin D receptor activator may be advisable during Cina withdrawal.

Osteoblastic differentiation of bone marrow mesenchymal stem cells in uremic rats.

Severe secondary hyperparathyroidism (SHPT) represents a high turnover bone disease, osteitis fibrosa, but the pathogenesis of osteitis fibrosa remains to be fully elucidated. We examined the characteristics of the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts in uremic rats. We bred 5/6 nephrectomized (Nx) rats with a high phosphorus (P) diet to induce SHPT (Nx + HP), or Nx (Nx + ND) and normal rats (Nc + ND) fed a standard diet (ND). After 8 weeks, BMSCs were isolated from the femur and serum were analyzed. BMSCs underwent flow cytometric examination for the expression patterns of cell surface markers (CD90+, CD29+, CD45-, and CD31-). Serum creatinine (Cre) levels were significantly elevated in the Nx + NP rats compared with the Nc + NP rats. Cre levels in the Nx + HP rats were levels to those in the Nx + ND rats. Serum P and PTH levels were significantly elevated in the Nx + HP rats compared with the Nx + ND rats. Bone morphometrical analysis showed increases in both osteoid volume and eroded surfaces in the Nx + HP but not in the Nx + ND rats. The populations of harvested BMSCs were similar between all three groups. Alp, Runx2, Pth1r and Cyclin D1 mRNA expression in the BMSCs from the Nx + ND rats were significantly suppressed compared with those isolated from the Nc + ND groups. Alizarin red staining tended to be similar to the expression of these mRNA. These results suggest that the BMSCs differentiation into osteoblasts was disturbed in the uremic rats.

Effect of Continuous Intravenous Calcium Loading on Fibroblast Growth Factor 23 in Normal and Uremic Rats.

Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with CKD. However, the mechanisms underlying stimulation of FGF23 remain to be investigated. We examined whether hypercalcemia induced by continuous intravenous (CIV) calcium (Ca) infusion regulates FGF23 levels in normal rats (Normal) and 5/6 nephrectomized uremic rats (Nx). Microinfusion pumps were implanted in the Normal and Nx rats for CIV Ca infusion, and blood, urine, kidney, and tibia were collected. The results showed an increase in serum Ca-stimulated FGF23 independently of serum phosphate (P) and creatinine levels in Normal and Nx rats. FGF23 mRNA from the tibia was also increased by the Ca infusion. Despite high FGF23 levels after Ca infusion, urinary P excretion was decreased. Renal α-Klotho expression was significantly reduced by Ca infusion. These results suggest that intravenous Ca loading might stimulate FGF23 production from bone in normal and uremic rats. Reduction of renal P excretion suggests that the bioactivity of FGF23 is inhibited, and the decrease in renal α-Klotho expression might have a role in this pathological process. In conclusion, CIV Ca loading increased FGF23 in normal and uremic rats, and renal α-Klotho is necessary to maintain the bioactivity of FGF23 as a phosphaturic factor.

Research on kidney and mineral metabolism in Japan: past, present, and future.

Since the identification of the kidney was the main site for the synthesis of calcitriol (1α, 25-dihydroxycholecalciferol), research on chronic kidney disease (CKD)-associated mineral metabolism disorders and their management has made rapid progress. Various active analogues of calcitriol have clinically become available for treating secondary hyperparathyroidism (SHPT), which is a representative mineral metabolism abnormality in CKD patients. A calcimimetic compound cinacalcet hydrochloride has also been developed for the medical management of SHPT through a different mechanism involving the calcium-sensing receptor. The concept of CKD-mineral and bone disorder (CKD-MBD) was proposed in 2006 to provide a comprehensive understanding of a disorder related to mineral metabolism abnormalities of CKD, based on the fact that these abnormalities are closely associated with cardiovascular disease as well as bone disorders (renal osteodystrophy). There has been a recent surge in the development of phosphate binders for CKD-MBD, focused on an effort to improve mortality. In Japan, high-quality basic and clinical research on CKD-MBD has led to the development of novel therapeutic drugs, such as maxacalcitol, falecalcitriol, and bixalomer. New practice guidelines have been published and are widely adapted in clinical practice.

The cardiothoracic ratio and all-cause and cardiovascular disease mortality in patients undergoing maintenance hemodialysis: results of the MBD-5D study.

BACKGROUND: The cardiothoracic ratio (CTR) is a non-invasive left ventricular hypertrophy index. However, whether CTR associates with cardiovascular disease (CVD) and mortality in hemodialysis (HD) populations is unclear. METHODS: Using a Mineral and Bone disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D Study) subcohort, 2266 prevalent HD patients (age 62.8 years, female 38.0%, HD duration 9.4 years) with secondary hyperparathyroidism (SHPT) whose baseline CTR had been recorded were selected. We evaluated associations between CTR and all-cause death, CVD death, or composite events in HD patients. RESULTS: CTR was associated significantly with various background and laboratory characteristics. All-cause death, CVD-related death, and composite events increased across the CTR quartiles (Q). Adjusted hazard risk (HR) for all-cause death was 1.4 (95% confidential interval, 0.9-2.1) in Q2, 1.9 (1.3-2.9) in Q3, and 2.6 (1.7-4.0) in Q4, respectively (Q1 as a reference). The corresponding adjusted HR for CVD-related death was 1.8 (0.8-4.2), 3.1 (1.4-6.8), and 3.5 (1.6-7.9), and that for composite outcome was 1.2 (1.0-1.6), 1.7 (1.3-2.2), and 1.8 (1.5-2.3), respectively. Exploratory analysis revealed that there were relationships between CTR and age, sex, body mass index, comorbidity of CVD, dialysis duration and intact parathyroid hormone, phosphorus, hemoglobin, and usage of phosphate binder [corrected]. CONCLUSION: CTR correlated with all-cause death, CVD death, and composite events in HD patients with SHPT.

Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats.

BACKGROUND: Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats. METHODS: Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed. RESULTS: Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion. CONCLUSIONS: These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23.

[New Developments in CKD-MBD. Future perspective of calcimimetics].

Calcimimetics have beneficial effects on not only secondary hyperparathyroidism, but also control of serum calcium and phosphate levels. Development of novel calcimimetics is progressing. Basic studies have demonstrated the direct effect of calcimimetics on the vascular tissues, which may contribute to the improvement of vascular calcification. Further studies are required to evaluate the usefulness of calcimimetics for mortality.

Long-Term Effect of Denosumab on Bone Disease in Patients with CKD.

BACKGROUND: The effect of long-term denosumab therapy and of denosumab discontinuation on the cortical bone of the hip regions in dialysis patients has not been studied. METHODS: This retrospective study investigated the cortical and trabecular compartments and estimated strength indices of the hip region, obtained using 3D-SHAPER software, after a maximum of 5 years of denosumab therapy in 124 dialysis patients. A Wilcoxon signed-rank test was used to identify the differences in each parameter before and after denosumab initiation. Similarly, we investigated the changes in these parameters after denosumab discontinuation in 11 dialysis patients. RESULTS: Integral and trabecular volumetric bone mineral densities (BMD) were significantly lower at the start of denosumab therapy than those in 1 year before denosumab initiation. After starting denosumab, areal BMD (median change +7.7% [interquartile range (IQR), +4.6 to +10.6]), cortical volumetric BMD (median change +3.4% [IQR, +1.0 to +4.7]), cortical surface BMD (median change +7.1% [IQR, +3.4 to +9.4]), and cortical thickness (median change +3.2% [IQR, +1.8 to +4.9]) showed a significantly higher trend for 3.5 years, which then stabilized at a higher value compared with baseline. A similar trend in the trabecular volumetric BMD (median change +9.8% [IQR, +3.8 to +15.7]) was observed over 2.5 years, with a higher value maintained thereafter. The whole area of the hip region improved after denosumab therapy. Similar trajectories were also found in the estimated strength indices. Conversely, at 1 year after denosumab discontinuation, these 3D parameters and estimated strength indices tended to largely worsen. The lateral aspect of the greater trochanter was the most pronounced location showing volumetric BMD loss. CONCLUSIONS: The BMD of both cortical and trabecular components in the hip region was significantly higher after starting denosumab therapy. However, these measurements exhibited a trend of declining substantially after the discontinuation of denosumab.

Vitamin D receptor activators inhibit vascular smooth muscle cell mineralization induced by phosphate and TNF-α.

BACKGROUND: Vascular calcification is a highly regulated process. Tumor necrosis factor-α (TNF-α) has been shown to accelerate the highly regulated osteogenic process in vascular smooth muscle cells (VSMCs). Vitamin D receptor activators (VDRAs) have been associated with beneficial cardiovascular outcomes in patients with chronic kidney disease. We examined whether maxacalcitol, a vitamin D(3) analog, exhibits a suppressive effect on VSMC mineralization induced by phosphate and TNF-α. METHODS: Human VSMCs were treated with either vehicle, maxacalcitol (10(-9) to 10(-7) M), or calcitriol (10(-9) to 10(-7) M) in 2.5 mM of phosphate media with TNF-α (1 ng/mL) for 9 days. VSMC mineralization was determined and expression of genes associated with the osteogenic process was examined by real-time reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-2 (MMP-2) messenger RNA (mRNA) in VSMCs and MMP-2 protein in media was also analyzed. RESULTS: Vehicle-treated VSMCs exhibited massive mineralization, which was inhibited by maxacalcitol in a concentration-dependent manner. Calcitriol also inhibited the mineralization. While vehicle-treated VSMCs exhibited increased mRNA expression of genes associated with the osteogenic process (Cbfa1/Runx2 and osteocalcin) compared with VSMCs grown in normal media without TNF-α (control), maxacalcitol and calcitriol suppressed the increase in mRNA species. Furthermore, vehicle-treated VSMCs exhibited increased MMP-2 mRNA and protein in the media that were suppressed notably by maxacalcitol. CONCLUSIONS: Both the VDRAs abrogated the acceleration of the osteogenic process induced by phosphate and TNF-α in VSMCs, which was linked to inhibition of mineralization in VSMCs. MMP-2 blockade by VDRAs may contribute to an inhibitory effect on vascular calcification.

Number of enlarged parathyroid glands might be a predictor of cinacalcet response in advanced secondary hyperparathyroidism.

BACKGROUND: Cinacalcet has been shown to be effective in lowering serum intact parathyroid hormone (iPTH) levels in patients with advanced secondary hyperparathyroidism (SHPT). We investigated clinical factors influencing therapeutic response to cinacalcet for SHPT refractory to active vitamin D sterols. METHODS: A total of 57 hemodialysis patients with SHPT (iPTH >300 pg/mL) were enrolled in this 28-week, prospective, observational study. Cinacalcet was started at an initial dose of 25 mg/day; the dose of cinacalcet was titrated to achieve the following: 3.5 ≤ phosphate (P) ≤ 6.0 mg/dL; 8.4 ≤ adjusted calcium (Ca) ≤ 10.0 mg/dL; 60 ≤ iPTH ≤ 180 pg/mL). Parathyroid ultrasonographic examination was performed at the start of cinacalcet treatment. Patients were divided into two groups on the basis of iPTH levels after 28 weeks: Group A, iPTH ≤180 pg/mL; Group B, iPTH >180 pg/mL. RESULTS: Serum iPTH and P levels at baseline were significantly higher in Group B than Group A. The number of enlarged parathyroid glands (PTGs) (estimated volume ≥500 mm(3) or major axis ≥10 mm), which presumably had nodular hyperplastic lesions, and the largest and the total volume of detectable PTGs were significantly greater in Group B compared with Group A. In our multivariate logistic regression analysis, patients with two or more enlarged PTGs had a significant risk of poor response to cinacalcet treatment (odds ratio 5.68, 95% confidence interval 1.19-32.66, P = 0.0363). CONCLUSION: These results indicate that the number of enlarged PTGs could predict therapeutic response of cinacalcet in patients with advanced SHPT.

[Phosphate sensing and parathyroid gland].

In the latter 1990s, phosphate, as well as calcium, has been shown to have a direct action on parathyroid function. Since then although many researchers have tried to detect the phosphate sensor in parathyroid gland, none has found it yet. In 2000s, the importance of FGF23 was revealed in patients with autosomal dominant hypophosphatemic rickets and then investigating the role of FGF23 in mineral metabolism has spread. FGF23 target organs comprise those that express coreceptor Klotho, such as kidney and parathyroid glands. While associations of calcium sensing receptor or vitamin D receptor with parathyroid function have been mainly investigated for parathyroid dysfunction, many efforts recently have made to study the effects of FGF23 on parathyroid glands.

Effects of calcimimetic combined with an angiotensin-converting enzyme inhibitor on uremic cardiomyopathy progression.

BACKGROUND/AIMS: Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective properties and functional calcium-sensing receptors express in cardiac myocytes. METHODS: Rats were made uremic by 5/6 nephrectomy and treated as follows: uremic rats were fed on a regular diet (UC), uremic + enalapril (E), uremic + calcimimetic agent R-568 (R-568), and uremic + enalapril + R-568 (E+R-568). A group of normal rats served as controls (NC). RESULTS: Blood pressure (BP) and left ventricle mass were elevated significantly in the UC and R-568 groups compared with those in the NC group, but were indistinguishable from normal controls in the E and E+R-568 groups. Cardiac fibrosis was significantly increased in the UC group compared with that in the NC group. This increase was significantly attenuated in the R-568 and E groups, and the attenuation was further enhanced in the E+R-568 group. Factors associated with cardiac hypertrophy such as proliferating cell nuclear antigen, cyclin D1, and cyclin D2, as well as factors associated with cardiac fibrosis such as type I collagen, fibronectin, and transforming growth factor-ß1 were significantly increased in the UC group compared with those in the NC group. Monotherapy with R-568 or E attenuated this increase and the combination further attenuated these measures. CONCLUSIONS: Calcimimetics can suppress the progression of uremic cardiomyopathy and this effect is amplified when BP is controlled via renin-angiotensin system blockade.