Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH >300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of <250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels <300 pg/ml (46 versus 9%), proportion of patients with >30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with >20, >40, or >50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH <300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca ؋ P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca ؋ P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.
Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.
Background/Aims: Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD). Methods: We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or presence of albuminuria (≥30 mg/24 h). Results: After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3–357.5) in patients with CKD and 119.4 ng/dl (103.7–134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = –0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of –26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2–45.5; p < 0.0001). Conclusion: These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.
Parameters of erythropoiesis were studied in patients with endstage renal disease established on continuous ambulatory peritoneal dialysis (CAPD) and regular hemodialysis treatment (RDT). Serum erythropoietin was measured by radioimmunoassay, and erythroid progenitor cell (CFU-E) formation was assayed in fetal mouse liver cultures. Serum erythropoietin concentrations in both CAPD (35.3 +/- 4.0 mU/ml) and RDT (31.9 +/- 1.9 mU/ml) patients were significantly higher (P less than 0.01) than normal values (23.1 +/- 1.0 mU/ml). The serum erythropoietin concentration did not correlate with either hematocrit or inhibition of CFU-E formation in either group of dialysis patients. In both CAPD and RDT patients the hematocrit correlated significantly (P less than 0.001) with the degree of serum inhibition of CFU-E formation. CFU-E formation decreased from 74.5 +/- 2.5 to 62.5 +/- 3.5% of control with increasing concentrations of uremic serum in cell cultures from 5 to 20%. In RDT patients a single hemodialysis produced a decrease in the mean serum erythropoietin concentration from 31.8 +/- 2.1 to 27.4 +/- 1.8 mU/ml (P less than 0.01) but no significant change in CFU-E formation. In conclusion, although serum immunoreactive erythropoietin levels are elevated above the normal range in dialysis patients, the response remains inadequate for the severity of the anemia, and it is the degree of serum inhibition of erythropoiesis in both CAPD and RDT patients which correlates with and possibly determines the degree of anemia.
Background & objectives: Chronic kidney disease (CKD) is commonly complicated by secondary hyperparathyroidism (SHPT), leading to increased risk of morbidity and mortality. SHPT is a progressive disease often requiring long-term therapy to control parathyroid hormone (PTH) and mineral imbalances. Vitamin D sterols and phosphate binders, used as traditional therapies to lower PTH and phosphorus, may provide inadequate long-term control for many dialysis patients. Cinacalcet, by simultaneously lowering PTH, calcium, phosphorus, and calcium-phosphorus levels, may maintain PTH and mineral balance in these individuals. However, as with traditional therapies, long-term data are limited.Design, setting, participants, & measurement: Dialysis subjects from at least one of five lead-in studies (double-blind placebo-controlled, including one extension trial) completing up to 52 wk of either cinacalcet or placebo were eligible for this open-label extension study, including an 8-wk dose titration (initiated at 30 mg/d), followed by 24-wk maintenance and up to 132 wk of follow-up. Final efficacy analysis was at week 180.Results: Three hundred thirty-four of 589 enrolled subjects received cinacalcet from the beginning of the lead-in study. Weekly median PTH values were <300 pg/ml (weeks 16 through 180) and median Ca؋P values were <55 mg 2 /dl 2 (weeks 4 through 180). Similar results were exhibited in the 255 subjects who initially received placebo. Among the patients exposed to cinacalcet from the beginning of the lead-in study, 3% of subjects exhibited treatment-related serious adverse events.Conclusions: Cinacalcet effectively maintained PTH, Ca and P reductions in dialysis subjects for up to 180 wk. Clin J Am Soc Nephrol 4: 1465-1476, 2009. doi: 10.2215 S econdary hyperparathyroidism (SHPT) occurs often in chronic kidney disease (CKD). It is characterized by increases in the synthesis and secretion of parathyroid hormone (PTH) and by disturbances in calcium (Ca), phosphorus (P), and vitamin D metabolism (1). SHPT is a progressive disorder among those undergoing dialysis in whom PTH levels increase by an average of 6% per year (2). Elevated PTH, Ca, P, and CaϫP levels and alterations in vitamin D metabolism are associated with important adverse outcomes, including cardiovascular disease, in such patients (3-6).The long-term efficacy and safety of traditional therapies for SHPT have not been critically examined. Despite many years of clinical use, results from prospective clinical trials describing therapeutic responses to any vitamin D sterol among dialysis patients with SHPT lasting more than 13 mo are available from only six patients after 2 yr of follow-up (20). Sustained treatment with vitamin D alone often proves inadequate for dialysis patients with SHPT (7-9). Disturbances in calcium and phosphorus metabolism frequently disrupt therapy (10), rendering consistent biochemical control of the disorder difficult (8).Treatment with cinacalcet hydrochloride (cinacalcet) often concurrently lowers PTH, Ca, P, and CaϫP levels a...
The improvement in the anemia in patients with end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) suggests that dialyzable substances present in the sera of uremic patients either inhibit erythropoiesis directly or inactivate erythropoietin (EPO). In the present study predialysis sera from patients with ESRD inhibited erythroid colony (CFU-E) (N = 10) formation to a significantly (P less than 0.01) greater degree than granulocyte-macrophage (CFU-GM) (N = 7) colony formation in mouse bone marrow (MBM) cultures. The polyamines spermine (SP) (18 to 560 nm/ml) and spermidine (SD) (4 to 648 nm/ml) exerted a more significant (P less than 0.05) inhibition of CFU-E (N greater than or equal to 5) than that of CFU-GM (N greater than or equal to 5) growth. Concentrations of 0.80, 1.0, and 1.5 nm/ml of putrescine (PU) were 92%, 85%, and 77% of erythroid colony (CFU-E) controls (N = 4) and 104%, 130%, and 127% of CFU-GM controls (N = 4). Putrescine (PU) at 1.5 nm/ml also produced a significant (P less than 0.05) inhibition of CFU-E, whereas CFU-GM were stimulated by PU. These data suggest that predialysis sera from uremic patients, as well as SP, SD, and PU, are selectively more inhibitory to CFU-E than CFU-GM growth. The immunoreactivity of EPO was not significantly changed when it was coincubated with SP, SD and PU and measured by radioimmunoassay. PU was found to inhibit noncompetitively the bioactivity of EPO in a CFU-E assay. These data support the hypothesis that polyamines may be important uremic toxins in the anemia of ESRD.
Early essential hypertension is asymptomatic and should remain so throughout treatment. In view of the increasing number of available antihypertensive agents, clinicians need to become familiar with the potential side effects of these drugs. By placing more emphasis on non-pharmacological treatment (sodium restriction, weight loss, exercise) and thoroughly evaluating each case in particular, the pharmacological regimen can be optimally tailored to the patient's needs. Potential side effects should be predicted and can often be avoided; if they become clinically significant they should be rapidly recognised and corrected. These side effects can be easily remembered in most instances, as they fall into 3 broad categories: (a) those caused by an exaggerated therapeutic effect; (b) those due to a non-therapeutic pharmacological effect; and (c) those caused by a non-therapeutic, non-pharmacological effect probably representing idiosyncratic reactions. This review focuses mainly on adverse effects of the second and third kind. Each group of drugs in general shares the common side effects of the first two categories, while each individual drug has its own idiosyncratic side effects.
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