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.

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.

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.

Lower soluble Klotho levels in the pretransplant period are associated with an increased risk of renal function decline in renal transplant patients.

Serum soluble Klotho levels are associated with renal function in predialysis patients with chronic kidney disease. However, few reports exist regarding the association between soluble Klotho levels and renal function in kidney transplant (KTx) recipients. This was a retrospective observational study of 41 living KTx recipients. The serum soluble Klotho levels were classed as "high" (>456 pg/mL [i.e., high-Klotho group]) or "low" (≤456 pg/mL [i.e., low-Klotho group]). Renal function decline was defined as a decrease in the estimated glomerular filtration rate (eGFR) of 30% or more from the baseline value within 3 months after KTx. A multivariable time-to-event analysis between the groups was conducted. Among the KTx recipients, the incidence of a 30% decrease in the eGFR was significantly higher in the low-Klotho group than in the high-Klotho group (P = .036). After adjusting for donor age, donor sex, the presence of rejection, and the number of cytomegalovirus infections, multivariable Cox models revealed that low soluble Klotho levels remained associated with a higher risk of a 30% decrease in the eGFR (hazard ratio, 2.38; 95% confidence interval, 1.02-6.41). These findings suggested that lower soluble Klotho levels in the pre-KTx period are associated with an increased risk of renal function decline in KTx recipients.

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.

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.

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.

Multidisciplinary management of calciphylaxis: a series of 5 patients at a single facility.

Calciphylaxis is a rare and severe disease that manifests with painful skin ulceration and necrosis. Herein, we report five patients of hemodialysis patients with skin biopsy-proven calciphylaxis at a single facility. One patient had undergone parathyroidectomy (PTx) due to severe secondary hyperparathyroidism, four had been treated with vitamin D receptor activators, and two were on warfarin therapy. All patients had hyperphosphatemia, and one had hypercalcemia. The intact parathyroid hormone level at diagnosis was 2 pg/ml in the patient after PTx, while three patients were within the target range. The average period after diagnosis of calciphylaxis was 2 months. Skin lesions were present on the thighs and lower legs in two patients, and on the dorsum of the foot in one patient. In skin biopsy, calcification was found in the arteriolar media in four patients, and calcium (Ca) was deposited in the dermal lesion in one patient. All patients received local cures, surgical debridement, antibiotics to control infectious diseases, and strict control of serum Ca and phosphate. Calcimimetics were used in all patients except one who had undergone PTx one month before, sodium thiosulfate was used in 4 patients, and low Ca dialysate was used in three patients. The average follow-up period was 7.4 months. Four patients were cured, and one died due to infection. We suggest that multidisciplinary management for infectious diseases, surgical debridement, strict control of mineral and bone markers from the early stage, and elimination of risk factors may improve the course of calciphylaxis, which is a life-threatening disease.

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment.

The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade-off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca-sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review.

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.

RAS Inhibitor Is Not Associated With Cardiovascular Benefits in Patients Undergoing Hemodialysis in Japan.

Definitive evidence of whether renin angiotensin system (RAS) inhibition is beneficial on cardiovascular events (CVE) among patients undergoing hemodialysis (HD) is lacking. The objective of this study was to investigate the association of RAS inhibitor usage with CVEs in patients enrolled in the Dialysis Outcomes Practice Pattern Study in Japan (J-DOPPS). Association of RAS inhibitor prescription with outcomes including all-cause death, death caused by CVE, and hospitalization due to cardiac failure was investigated by using a multivariable Cox proportional hazards model. Of the 3848 patients enrolled, 1784 (45%) patients were treated by RAS inhibitors. After adjusting for potential cofounders by Cox proportional hazards models, we found a statistically insignificant but positive association of RAS inhibitor usage with death caused by CVE (HR: 1.46, 95%CI: 0.96-2.23, P = 0.08). Similar results were observed in the association of RAS inhibitor with all-cause death, hospitalization due to cardiac failure, and hospitalization due to CV disease (HR for all-cause death: 1.24, 95%CI: 0.84-1.48, P = 0.28, HR for hospitalization due to cardiac failure: 1.24, 95%CI: 0.84-1.81, P = 0.28, and HR for hospitalization due to CV disease: 1.20, 95%CI: 0.95-1.51, P = 0.13). Sensitivity analyses using propensity scores gave similar results. RAS inhibition did not show favorable association with CVEs suggesting that RAS inhibition alone was insufficient to reduce the risk of CV complications in patients undergoing HD. Some strategies in addition to RAS inhibition may be needed to protect against CVEs in this population.

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.

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.

Cardiac effect of vitamin D receptor modulators in uremic rats.

Vitamin D receptor (VDR) modulators (VDRMs) are commonly used to control secondary hyperparathyroidism (SHPT) associated with chronic kidney disease, and are associated with beneficial outcomes in cardiovascular disease. In this study, we compared the cardiac effect of VS-105, a novel VDRM, with that of paricalcitol in 5/6 nephrectomized uremic rats. Male Sprague-Dawley rats were 5/6 nephrectomized, fed a standard diet for 4 weeks to establish uremia, and then treated (intraperitoneally, 3 times/week) with vehicle (propylene glycol), paricalcitol (0.025 and 0.15µg/kg), or VS-105 (0.05 and 0.3µg/kg) for 4 weeks. In uremic rats, neither VDRM (low and high doses) altered serum creatinine and phosphorus levels. Serum calcium was significantly higher with high dose paricalcitol compared to sham rats. PTH levels were significantly decreased with low dose paricalcitol and VS-105, and were further reduced in the high dose groups. Interestingly, serum FGF23 was significantly higher with high dose paricalcitol compared to sham rats, whereas VS-105 had no significant effect on FGF23 levels. Left ventricle (LV) weight and LV mass index determined by echocardiography were significantly suppressed in both high dose VDRM groups. This suppression was more evident with VS-105. Western blotting showed significant decreases in a fibrosis marker TGF-ß1 in both high dose VDRM groups (vs. vehicle) and Masson trichrome staining showed significant decreases in cardiac fibrosis in these groups. These results suggest that VS-105 is less hypercalcemic than paricalcitol and has favorable effects on SHPT and cardiac parameters that are similar to those of paricalcitol in uremic rats. The cardioprotective effect is a noteworthy characteristic of VS-105.

PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.