Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis.

BACKGROUND: Secondary hyperparathyroidism develops early in patients with chronic kidney disease (CKD). Clinical guidelines from the National Kidney Foundation-Kidney/Disease Outcomes Quality Initiative emphasize the need to control parathyroid hormone (PTH), calcium, and phosphorus levels in patients with CKD not receiving dialysis to reduce poor outcomes. This phase 2 study evaluated the effects of the oral calcimimetic cinacalcet hydrochloride in patients with CKD not on dialysis therapy. METHODS: A randomized, double-blind, placebo-controlled, 18-week study enrolled adults with an estimated glomerular filtration rate of 15 to 50 mL/min/1.73 m2 (0.25 to 0.83 mL/s/1.73 m2) and an intact PTH (iPTH) level greater than 130 pg/mL (ng/L). Cinacalcet (or placebo) was titrated from 30 to 180 mg once daily to obtain a 30% or greater reduction in iPTH levels from baseline. RESULTS: Baseline mean iPTH levels were 243 pg/mL (ng/L) in the cinacalcet group (n = 27) and 236 pg/mL (ng/L) in the control group (n = 27). At baseline, 28% of subjects were being administered vitamin D sterols and 43% were being administered phosphate binders or calcium supplements. The addition of cinacalcet significantly decreased iPTH concentrations compared with controls during the efficacy-assessment phase: 56% versus 19% of subjects achieved a 30% or greater reduction in iPTH levels (P = 0.006), and mean iPTH levels decreased by 32% in the cinacalcet group, but increased by 6% in the control group (P < 0.001). Mean serum calcium and phosphorus levels remained within normal range throughout the study. Cinacalcet generally was well tolerated; the most frequent adverse events were gastrointestinal. CONCLUSION: This preliminary study provides evidence that cinacalcet is efficacious for the treatment of secondary hyperparathyroidism in subjects with CKD not receiving dialysis.

Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study.

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 > or =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 < or =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 < or =300 pg/ml (46 versus 9%), proportion of patients with > or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with > or =20, > or =40, or > or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x 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 x 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.

Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism.

Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30-50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium

Slowing the progression of diabetic nephropathy and its cardiovascular consequences.

This paper incorporates the findings from a multidisciplinary meeting on diabetic nephropathy and its renal and cardiovascular complications into a review article. The epidemic of obesity and the growing elderly population in the United States are primary drivers of a secondary epidemic of incipient type 2 diabetes mellitus and diabetic nephropathy. Current therapies aim to treat blood pressure, particularly with agents that block the renin-angiotensin system, to a target of 130/80 mm Hg. However, even lower blood pressure targets may be optimal. Control of hyperglycemia and dyslipidemia, smoking cessation, exercise, and weight loss all compliment blood pressure control and are achieved most effectively when the patient, provider, and health system are aligned with these goals. Once end-stage renal disease (ESRD) is reached, patients enter the highest cardiovascular risk-state appreciated in human medicine. Because of uniform access to care in the United States, advanced data systems, and circulatory system (intravascular) access in most patients, the ESRD population should be the future sampling frame for newer treatments tested in both prospective cohort and randomized trials. Cardiorenal risk, or the degree of excess cardiovascular risk incurred by patients with chronic kidney disease and ESRD, is a state offering considerable research opportunities for novel cardiovascular risk factors. Future studies should fully consider the possibility that improved outcomes would be achieved at a greater cost; thus, cost-effectiveness studies are essential for understanding the economic aspects of implementation. The goal of an ideal clinical trial would be ESRD prevention; however, pragmatic objectives such as a greater understanding of therapeutic toxicities should also be explored in this population.

Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.

Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.

Characteristics of treated hypertension in incident hemodialysis and peritoneal dialysis patients.

BACKGROUND: The treatment of hypertension in dialysis patients is prevalent and poorly characterized. beta-Blockers and calcium channel blockers (CCBs) have been associated with reduced all-cause and cardiovascular mortality. This study describes the treatment of hypertension and assesses the association between mortality and class of antihypertensive medication among a cohort of dialysis patients. METHODS: The US Renal Data System (USRDS) Dialysis Morbidity and Mortality Study Wave II cohort was analyzed. A total of 2,877 patients initiating hemodialysis or peritoneal dialysis in 1996 or 1997 and treated with antihypertensives were included in this analysis. Vital status was followed until November 2000. RESULTS: Calcium channel blockers were prescribed to 70.3% of patients. Only 31.5% and 27.0% of patients with cardiovascular disease were prescribed angiotensin-converting enzyme inhibitors and beta-blockers, respectively. Mono-, double-, triple-, and more than triple-therapy were reported in 48.0%, 36.1%, 13.2%, and 2.7% of the cohort, respectively. In multivariable, fully adjusted models, no individual class of antihypertensives was associated with changes in all-cause mortality. In all patients, nondihydropyridine CCBs (non-DHP CCBs) were associated with a reduced risk of cardiovascular death (hazard ratio, 0.78; 95% confidence interval, 0.62 to 0.97) and among end-stage renal disease patients with preexisting cardiovascular disease, dihydropyridine CCBs (DHP CCBs) and non-DHP CCBs were associated with reduced risk of all-cause and cardiovascular mortality. CONCLUSION: Calcium channel blocker use is widespread among hypertensive dialysis patients. Antihypertensive prescription patterns suggest a lack of consensus regarding treatment of hypertension. Multivariable analysis of associations between antihypertensive class and mortality reveals results of uncertain clinical significance. Hypertension treatment trials in dialysis patients should be performed to appropriately inform treatment decisions.

Interactions between dialysis-related volume exposures, nutritional surrogates and mortality among ESRD patients.

BACKGROUND: Interdialytic weight gain is used as a surrogate for volume expansion in haemodialysis patients and as an indicator of non-compliance. Increased weight gain is associated with both a greater mortality risk and better nutrition indices. This analysis characterizes the association between dialysis-related volume expansion and mortality in the context of its interaction with nutritional surrogates. METHODS: All patients receiving haemodialysis through Fresenius Medical Care-North America during 1998 were included. The percentage reduction in weight or intradialytic weight loss (IDWL%) was defined as the difference between the average of pre- and post-dialysis weights from the last 3 months of 1997 expressed as a percentage of post-dialysis weight. Associations between IDWL% and clinical and demographic variables were estimated using linear regression. The association between mortality risk and IDWL% was estimated using Cox proportional hazards regression. RESULTS: Younger age, male gender, the presence of diabetes mellitus, decreasing cholesterol, post-dialysis weight and pre-dialysis blood pressure (systolic and pulse pressure) were associated with increased IDWL%. Increasing IDWL% was associated with increasing phosphorus, creatinine, albumin, potassium and urea reduction ratio. Increasing IDWL% was significantly associated with mortality at 1 year [hazard ratio (HR) = 1.07, P = 0.003]. Among patients with diabetes mellitus, increasing IDWL% was associated with a mortality HR of 1.03 (P = 0.02). Among patients without diabetes mellitus, increasing IDWL% was not associated with an increased mortality risk. Increasing IDWL% is associated with a greater mortality risk among patients with creatinine <7.26, which failed to remain significant for patients whose creatinine was >or=7.26 mg/dl. Increasing IDWL% is associated with a greater mortality risk among patients with greater post-dialysis weight, greater body mass index and lower serum sodium measurements. CONCLUSIONS: This study confirms and extends the findings of the deleterious association between increasing IDWL% and mortality among patients with diabetes mellitus and among subgroups based on serum creatinine and body weight. The putative deleterious effect of dialysis-related volume expansion on mortality must be interpreted in the context of the patient's diabetic and nutritional status.

White blood cells as a novel mortality predictor in haemodialysis patients.

BACKGROUND: Many conventional cardiovascular risk factors in the general population are not as predictive in end-stage renal disease (ESRD). As absolute neutrophil count and total white blood cell (WBC) count are associated with adverse cardiovascular outcomes and all-cause mortality, this analysis was undertaken to explore the associations of WBC variables with mortality risk in ESRD. METHODS: Of a total study population of 44 114 ESRD patients receiving haemodialysis during 1998 at facilities operated by Fresenius Medical Care, North America, 25 661 patients who underwent differential white cell count and had complete follow-up were included. Information on case mix (age, gender, race), clinical (diabetes, body mass index), and laboratory variables (haematocrit, albumin, creatinine, potassium, calcium, phosphorus, bicarbonate, ferritin, transferrin saturation and differential WBC count) was obtained. Associations between lymphocyte count, neutrophil count and demographic and clinical variables were examined using linear regression. Associations between WBC variables and survival were estimated using Cox proportional hazard regression. RESULTS: A higher lymphocyte count was associated with higher serum albumin and creatinine, lower age and black race. High neutrophil count was associated with lower serum albumin and creatinine, younger age and white race (all Ps <0.0001). Cox proportional hazard regression showed an increased lymphocyte count was associated with reduced mortality risk [HR 0.86 (0.83-0.89) per 500/ml increase in lymphocyte count] and an increased neutrophil count was associated with increased mortality risk [HR 1.08 (1.06-1.09) per 1000/ml increase in neutrophil count]. CONCLUSIONS: An increased neutrophil count is strongly associated with, and reduced lymphocyte count associated less strongly with, many surrogates of both malnutrition and inflammation. An increased neutrophil count and reduced lymphocyte count are independent predictors of increased mortality risk in haemodialysis patients.

Regional variability in anaemia management and haemoglobin in the US.

BACKGROUND: Regional differences in haemoglobin values and process care measures were examined using data from the Centers for Medicare & Medicaid Services' End-Stage Renal Disease (ESRD) Clinical Performance Measures Project. It was posited that regional differences in haemoglobin values are consequent upon differences in components of clinical practice. METHODS: A national random sample of 8336 adult, in-centre haemodialysis patients, stratified by the 18 regional ESRD Networks, was drawn. Information was collected for October-December 1998. Multivariable stepwise linear and logistic regression analyses were performed to identify variables associated with haemoglobin. Linear regression analysis was used to identify variables associated with Epo/Hb index (mean weight-adjusted treatment level erythropoietin (Epo) dose divided by mean haemoglobin). RESULTS: The percentage of patients with haemoglobin concentration < 11 g/dl ranged from 34 to 52% across ESRD Networks. In addition to haemoglobin there was significant, non-random variation among ESRD Networks with regard to prescribed Epo dose and administration route, intravenous (IV) iron prescription and dialyser flux (high flux = KUf > or = 20 ml/mmHg/h) (all P-values < 0.001). Higher haemoglobin was associated with older age, male gender, higher serum albumin, higher transferrin saturation, higher Kt/V, lower serum ferritin and lower prescribed Epo dose (all P-values < 0.01). Diabetes mellitus as cause of ESRD, high-flux dialyser use, IV iron prescription or subcutaneous Epo prescription were not associated with haemoglobin. Male gender, diabetes as cause of ESRD, older age, higher transferrin saturation and higher albumin concentrations were associated with lower Epo/Hb index. Prescription of IV iron and IV Epo were associated with higher Epo/Hb index. CONCLUSIONS: Regional mean haemoglobin levels vary considerably across the US and the variation in haemoglobin is explained by both non-modifiable factors and modifiable clinical practice-derived variables.

Trends in anemia management among US hemodialysis patients.

This study was undertaken to describe the relationship between hematocrit (Hct) and changes in the prescribed dose of erythropoietin (EPO) as well as selected patient and process care measures across annual national samples of hemodialysis patients from 1994 to 1998. This study uses the cohorts identified in the ESRD Core Indicators Project, random samples of 6181, 6241, 6364, 6634, and 7660 patients, stratified by ESRD Networks drawn for each year from 1994 to 1998. Patient demographic and clinical information was collected from October to December for each year. Surrogates of iron stores and patterns of iron and EPO administration were profiled from 1996 to 1998. Multivariable stepwise linear regression analyses were performed to adjust for potential confounding variables and to identify independent variables associated with Hct and EPO dose. Mean Hct and EPO dose increased each year from 31.1 +/- 5.2% to 34.1 +/- 3.7% and from 58.2 +/- 41.8 U/kg to 68.2 +/- 55.0 U/kg, respectively (P = 0.0001). Increasing Hct was positively associated with male gender, more years on dialysis, older age, higher urea reduction ratio and transferrin saturation, prescription of intravenous iron, and lower ferritin and EPO dose in multivariable models (all P = 0.0001). Male gender, older age, diabetes, higher Hct, and increasing weight, urea reduction ration, and transferrin saturation were associated with lower EPO doses (all P < 0.01). Conversely, intravenous EPO and iron were associated with higher prescribed EPO doses (all P = 0.0001). Although increasing Hct is associated with decreasing EPO dose at the patient level, the increase in Hct seen across years among the cohorts of hemodialysis patients in the United States has been associated with increasing doses of EPO at the population level.

Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis.

CONTEXT: Although increased blood pressure is associated with adverse outcomes in the general population, elevated blood pressure is associated with decreased mortality in patients with end-stage renal disease undergoing maintenance hemodialysis. Recent investigations in the general population have demonstrated the predictive utility of pulse pressure (systolic minus diastolic blood pressure), a measure reflecting the pulsatile nature of the cardiac cycle. OBJECTIVES: To estimate the relationship between pulse pressure and mortality in patients undergoing maintenance hemodialysis and to test our hypothesis that an increasing pulse pressure would be associated with increased risk of death up to 1 year despite the inverse relationship between conventional blood pressure measures and mortality in patients with end-stage renal disease. DESIGN, SETTING, AND PATIENTS: Retrospective cohort investigation of patients with end-stage renal disease undergoing maintenance hemodialysis at 782 hemodialysis facilities throughout the United States. Of 44 069 eligible patients as of January 1, 1998, 37 069 with complete demographic data were included in the analyses of clinical and laboratory data collected from October 1 through December 31, 1997. Patients were followed up through December 31, 1998. MAIN OUTCOME MEASURES: The primary study outcome was death at 1 year. A secondary outcome was the magnitude of the pulse pressure. RESULTS: The final patient cohort was similar to national averages with respect to age, sex, race, and diabetic status. Mean (SD) pulse pressures before dialysis were 75.0 (15.0) mm Hg and 66.9 (13.9) mm Hg after dialysis. By the end of the 1-year follow-up, 5731 patients (18.4%) died. After adjusting for level of systolic blood pressure, multivariable Cox proportional hazards modeling showed a direct and consistent relationship between increasing pulse pressure and increasing death risk. Each incremental elevation of 10 mm Hg in postdialysis pulse pressure was associated with a 12% increase in the hazard for death (hazard ratio, 1.12; 95% confidence interval, 1.06-1.18). Postdialysis systolic blood pressure was inversely related to mortality with a 13% decreased hazard for death for each incremental elevation of 10 mm Hg (hazard ratio, 0.87; 95% confidence interval, 0.84-0.90). In a multivariable linear regression model, important variables directly associated with elevated pulse pressure included age, diabetes, white race, female sex, and number of years receiving dialysis (all P<.001). CONCLUSIONS: Pulse pressure is associated with risk of death in a large, nationally representative sample of patients undergoing maintenance hemodialysis. The recognition of pulse pressure as an important correlate of mortality in patients receiving dialysis highlights the need to investigate the relationship between potential therapeutic implications of conduit vessel function and clinical outcomes in patients with end-stage renal disease.

Predictors of proteinuria and renal failure among women with HIV infection.

BACKGROUND: Glomerular disease with proteinuria and renal failure are complications of human immunodeficiency virus (HIV) infection. While studies suggest risk factors for both include black race and lower CD4 lymphocyte count, they have not been established in population-based cohorts. This study examines the risk factors for proteinuria and renal failure in a large cohort of HIV-infected women not selected for the presence of renal disease. METHODS: This prospective cohort includes 2059 women enrolled in the Women's Interagency HIV study (WIHS). WIHS is a longitudinal study of the clinical course of HIV infection in which subjects are followed biannually with a detailed exam including urine analysis, serum creatinine, CD4 lymphocyte count, and HIV RNA level. Proteinuria was defined as > or =+1 on urine dipstick exam on at least two consecutive urine analyses, and renal failure was defined as a doubling of serum creatinine. Multivariable logistic regression was used to estimate the associations between clinical variables and the presence of proteinuria on initial evaluation in a cross-sectional analysis. Cox proportional hazards regression was used to estimate the associations between clinical variables and time to renal failure among study participants with proteinuria in a prospective longitudinal analysis. RESULTS: Of 2057 HIV-positive women, 32% (N=671) had proteinuria on initial evaluation. Predictors of proteinuria include increasing (log) HIV RNA level [odds ratio (OR)=1.05], black race (OR=2.0), absolute CD4 lymphocyte count < or =200 cells/mm3 (OR=1.41), and the presence of hepatitis C antibody (OR=1.27; all P < 0.0001). Absolute CD4 lymphocyte count < or =200 cells/mm3 [hazard ratio (HR)=3.57, P=0.001], detectable HIV RNA level (HR=2.33, P=0.02), increasing systolic blood pressure (HR=1.02, P=0.002), and decreasing albumin (HR=3.33, P=0.0001) and increasing creatinine (1.67, P=0.0001) were all associated with the development of renal failure. CONCLUSIONS: This analysis establishes the associations between both increasing HIV RNA level and decreasing CD4 lymphocyte count with the presence of proteinuria and occurrence of renal failure. Additionally, it demonstrates an association between proteinuria and a positive hepatitis C antibody. To lessen the presence and progression of renal disease among HIV-infected patients, future research should focus on suppression of the HIV RNA level and improvement in CD4 lymphocyte count.