Overcoming Barriers in Kidney Health-Forging a Platform for Innovation.

Innovation in kidney diseases is not commensurate with the effect of these diseases on human health and mortality or innovation in other key therapeutic areas. A primary cause of the dearth in innovation is that kidney diseases disproportionately affect a demographic that is largely disenfranchised, lacking sufficient advocacy, public attention, and funding. A secondary and likely consequent cause is that the existing infrastructure supporting nephrology research pales in comparison with those for other internal medicine specialties, especially cardiology and oncology. Citing such inequities, however, is not enough. Changing the status quo will require a coordinated effort to identify and redress the existing deficits. Specifically, these deficits relate to the need to further develop and improve the following: understanding of the disease mechanisms and pathophysiology, patient engagement and activism, clinical trial infrastructure, and investigational clinical trial designs as well as coordinated efforts among critical stakeholders. This paper identifies potential solutions to these barriers, some of which are already underway through the Kidney Health Initiative. The Kidney Health Initiative is unique and will serve as a current and future platform from which to overcome these barriers to innovation in nephrology.

Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial.

Importance: Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective: To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet. Design, Setting, and Participants: A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015. Interventions: Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures: The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting. Results: The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT1896232.

Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials.

Importance: Secondary hyperparathyroidism contributes to extraskeletal complications in chronic kidney disease. Objective: To evaluate the effect of the intravenous calcimimetic etelcalcetide on serum parathyroid hormone (PTH) concentrations in patients receiving hemodialysis. Design, Setting, and Participants: Two parallel, phase 3, randomized, placebo-controlled treatment trials were conducted in 1023 patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism. Trial A was conducted in 508 patients at 111 sites in the United States, Canada, Europe, Israel, Russia, and Australia from March 12, 2013, to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013, to May 12, 2014. Interventions: Intravenous administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks. Main Outcomes and Measures: The primary efficacy end point was the proportion of patients achieving greater than 30% reduction from baseline in mean PTH during weeks 20-27. A secondary efficacy end point was the proportion of patients achieving mean PTH of 300 pg/mL or lower. Results: The mean age of the 1023 patients was 58.2 (SD, 14.4) years and 60.4% were men. Mean PTH concentrations at baseline and during weeks 20-27 were 849 and 384 pg/mL vs 820 and 897 pg/mL in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/mL vs 852 and 960 pg/mL in trial B. Patients randomized to etelcalcetide were significantly more likely to achieve the primary efficacy end point: in trial A, 188 of 254 (74.0%) vs 21 of 254 (8.3%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.4%-72.1%) and in trial B, 192 of 255 (75.3%) vs 25 of 260 (9.6%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.3%-72.1%). Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/mL or lower: in trial A, 126 of 254 (49.6%) vs 13 of 254 (5.1%; P < .001), for a difference in proportions of 44.5% (95% CI, 37.8%-51.2%) and in trial B, 136 of 255 (53.3%) vs 12 of 260 (4.6%; P < .001), for a difference in proportions of 48.7% (95% CI, 42.1%-55.4%). In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3%), and vomiting (10.4% and 7.5% vs 7.1% and 3.1%). Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration: clinicaltrials.gov Identifiers: NCT01788046.

C-Reactive Protein and Risk of ESRD: Results From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BACKGROUND: To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). STUDY DESIGN: Post hoc analysis of a randomized controlled trial. SETTING & PARTICIPANTS: 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. PREDICTOR: Baseline serum CRP concentrations. OUTCOMES: The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. MEASUREMENTS: We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. RESULTS: Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0mg/L, those with moderately/markedly elevated CRP levels (≥6.9mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. LIMITATIONS: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. CONCLUSIONS: Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD.

Race and ethnicity influences on cardiovascular and renal events in patients with diabetes mellitus.

BACKGROUND: The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD. METHODS: TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level ≤11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes. RESULTS: Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics. CONCLUSION: Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.

Treatment of Secondary Hyperparathyroidism: Results of a Phase 2 Trial Evaluating an Intravenous Peptide Agonist of the Calcium-Sensing Receptor.

BACKGROUND/AIMS: This study evaluated the efficacy and safety of AMG416 (etelcalcitide), a novel peptide agonist of the calcium (Ca)-sensing receptor given intravenously (IV) after each hemodialysis session for the treatment of secondary hyperparathyroidism (SHPT). METHODS: Adult subjects with SHPT on hemodialysis enrolled in a 12-week, dose titration (parent) study followed by an open-label extension phase. AMG416 was administered IV, thrice weekly starting at 5 mg/session and titrated based on the subject's parathyroid hormone (PTH) and albumin-corrected Ca (cCa) to target a PTH of 150-300 pg/ml. Efficacy (percent PTH change from baseline to the efficacy analysis period during the parent study) and safety (open-label extension phase) endpoints were evaluated. RESULTS: Baseline (n = 37) mean (standard error [SE]) PTH was 853 (106 pg/ml). The mean (95% CI) percent change from baseline to the efficacy analysis period in PTH concentration was -53.6% (-60.8, -46.4). The proportion of subjects with ≥30% reduction in PTH from baseline to the efficacy assessment period (EAP) was 89% (32/36; 95% CI 73.9, 96.9). Results by the baseline PTH subgroup (≤700 vs. >700 pg/ml) were comparable for both analyses. The proportion of subjects achieving a PTH ≤300 pg/ml was 56% (n = 20/36) at the efficacy assessment period. The mean (SE) percent changes from baseline to EAP were observed for cCa -15% (1.0%) and phosphorus -10% (3.3%). Adverse events were mild to moderate in severity. The PTH reductions achieved in the parent study were maintained in the open-label extension phase. CONCLUSION: AMG416 was well tolerated and appears to be an effective agent for the treatment of SHPT in patients on hemodialysis.

A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

BACKGROUND: Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. METHODS: In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. RESULTS: Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. CONCLUSIONS: The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Albuminuria and racial disparities in the risk for ESRD.

The causes of the increased risk for ESRD among African Americans are not completely understood. Here, we examined whether higher levels of urinary albumin excretion among African Americans contributes to this disparity. We analyzed data from 27,911 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had urinary albumin-to-creatinine ratio (ACR) and estimated GFR (eGFR) measured at baseline. We identified incident cases of ESRD through linkage with the United States Renal Data System. At baseline, African Americans were less likely to have an eGFR <60 ml/min per 1.73 m(2) but more likely to have an ACR ≥ 30 mg/g. The incidence rates of ESRD among African Americans and whites were 204 and 58.6 cases per 100,000 person-years, respectively. After adjustment for age and gender, African Americans had a fourfold greater risk for developing ESRD (HR 4.0; 95% CI 2.8 to 5.9) compared with whites. Additional adjustment for either eGFR or ACR reduced the risk associated with African-American race to 2.3-fold (95% CI 1.5 to 3.3) or 1.8-fold (95% CI 1.2 to 2.7), respectively. Adjustment for both ACR and eGFR reduced the race-associated risk to 1.6-fold (95% CI 1.1 to 2.4). Finally, in a model that further adjusted for both eGFR and ACR, hypertension, diabetes, family income, and educational status, African-American race associated with a nonsignificant 1.4-fold (95% CI 0.9 to 2.3) higher risk for ESRD. In conclusion, the increased prevalence of albuminuria may be an important contributor to the higher risk for ESRD experienced by African Americans.

Association between cardiac biomarkers and the development of ESRD in patients with type 2 diabetes mellitus, anemia, and CKD.

BACKGROUND: In patients with chronic kidney disease (CKD), as in other populations, elevations in cardiac biomarker levels predict increased risk of cardiovascular events. We examined the value of troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in assessing the risk of developing end-stage renal disease (ESRD) in diabetic patients with CKD. STUDY DESIGN: Prospective cohort study nested within a randomized clinical trial. SETTING & PARTICIPANTS: Patients with type 2 diabetes, CKD (estimated glomerular filtration rate [eGFR], 20-60 mL/min/1.73 m(2)), and anemia enrolled in TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy). PREDICTORS: Serum levels of the cardiac biomarkers TnT and NT-pro-BNP. OUTCOMES: Incidence of ESRD and the composite of death or ESRD. MEASUREMENTS: We measured TnT and NT-pro-BNP in baseline serum samples from the first 1,000 patients enrolled in TREAT. The relationship of these cardiac biomarker levels to the development of ESRD and death or ESRD was analyzed in multivariable regression models. RESULTS: Detectable TnT (≥0.01 ng/mL) was present in 45% of participants, and median NT-pro-BNP level was elevated at 605 pg/mL. Higher levels of both cardiac biomarkers were associated independently with higher rates of ESRD, as well as death or ESRD, and remained prognostically important after adjustment for eGFR, proteinuria, and other known predictors of CKD progression. The addition of cardiac biomarkers to a multivariable model for prediction of ESRD improved discrimination of those with and without an event by 16.9% (95% CI, 6.3%-27.4%). LIMITATIONS: Observational study in a clinical trial cohort; results require validation. CONCLUSIONS: In ambulatory patients with type 2 diabetes, anemia, and CKD, TnT and NT-pro-BNP levels frequently are elevated. These cardiac-derived biomarkers enhance prediction of ESRD beyond established risk factors. Measurement of TnT and NT-pro-BNP may improve the identification of patients with CKD who are likely to require renal replacement therapy, supporting a link between cardiac injury and the development of ESRD.

Changes in erythropoiesis-stimulating agent (ESA) dosing and haemoglobin levels in US non-dialysis chronic kidney disease patients between 2005 and 2009.

BACKGROUND: Recent clinical trials in cancer patients treated with erythropoiesis-stimulating agents (ESAs) and in CKD patients treated to haemoglobin (Hb) targets above the labeled range of 10-12 g/dL with ESAs raised safety concerns regarding ESA therapy. Subsequently, product labeling was revised including addition of a black-box warning and removal of many quality of life claims not supported by current standards, and there were changes in reimbursement and anaemia guidelines. The extent to which these events influenced ESA dosing and Hb levels in patients with chronic kidney disease not on dialysis (CKD-NOD) is not known. METHODS: We used data collected in a series of cross-sectional surveys between March 2005 and July 2009. Patients with CKD-NOD were selected from a random sample of free-standing US nephrology clinics. Information on demographics, insurance information, laboratory data and ESA use was abstracted from medical records by site investigators. We evaluated ESA treatment (use and dosing) and Hb levels over time and used multivariate linear regression to assess changes in ESA doses and Hb levels over time adjusting for case-mix differences. RESULTS: Between 2005 and 2009, 15 836 CKD-NOD patients were sampled. During this period, ESA use declined from 60 to 46%, and the mean dose declined from 176 to 136 mcg/month; the largest decline in use and in dose occurred beginning in 2007. Simultaneously, the mean (standard deviation) Hb level in ESA-treated patients declined from 11.5 (1.4) to 10.6 (1.2) g/dL, though the decline was most pronounced starting in 2007. As the mean Hb declined, the percent of treated patients with an Hb > 12 g/dL dropped from 27 to 12%, and the mean dose in this sub-population declined from 173 to 111 mcg/month. CONCLUSION: The emergence of safety concerns and the subsequent changes in product labeling, reimbursement and clinical practice guidelines all appear to have influenced physician dosing practices resulting in less frequent use of ESAs, lower ESA doses and lower achieved Hb levels in CKD-NOD patients.

Kidney function, albuminuria, and all-cause mortality in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study.

BACKGROUND: Chronic kidney disease and albuminuria are associated with increased risk of all-cause mortality. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 17,393 participants (mean age, 64.3 ± 9.6 years) in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study. PREDICTOR: Estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (ACR). OUTCOME: All-cause mortality (710 deaths); median duration of follow-up, 3.6 years. MEASUREMENTS & ANALYSIS: Categories of eGFR (90 to <120, 60 to <90, 45 to <60, 30 to <45, and 15 to <30 mL/min/1.73 m(2)) and urinary ACR (<10 mg/g or normal, 10 to <30 mg/g or high normal, 30 to 300 mg/g or high, and >300 mg/g or very high). Cox proportional hazards models were adjusted for demographic factors, cardiovascular covariates, and hemoglobin level. RESULTS: The background all-cause mortality rate for participants with normal ACR, eGFR of 90 to <120 mL/min/1.73 m(2), and no coronary heart disease was 4.3 deaths/1,000 person-years. Higher ACR was associated with an increased multivariable-adjusted HR for all-cause mortality within each eGFR category. Decreased eGFR was associated with a higher adjusted HR for all-cause mortality for participants with high-normal (P = 0.01) and high (P < 0.001) ACRs, but not those with normal or very high ACRs. LIMITATIONS: Only 1 laboratory assessment for serum creatinine and ACR was available. CONCLUSIONS: Increased albuminuria was an independent risk factor for all-cause mortality. Decreased eGFR was associated with increased mortality risk in those with high-normal and high ACRs. The mortality rate was low in the normal-ACR group and increased in the very-high-ACR group, but did not vary with eGFR in these groups.

Baseline characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BACKGROUND: Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes. STUDY DESIGN: Randomized trial. SETTING & PARTICIPANTS: 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries. INTERVENTION: Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo. OUTCOMES: TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point. CONCLUSIONS: With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia.

Chronic kidney disease and US healthcare resource utilization in a nationally representative sample.

BACKGROUND: Chronic kidney disease (CKD) is a prevalent condition; however, little is known about healthcare resource utilization (HRU) by CKD patients. METHODS: This analysis included NHANES participants aged > or =18 years, with serum creatinine, urine protein, and hemoglobin measurements. We assessed the association between CKD (stratified by stage) and HRU based on self-reported physician visits and hospitalizations in the year preceding the survey. RESULTS: Of the 15,258 included in this analysis, 2,110 had early CKD (stage 1 and 2 CKD) and 1,121 had late CKD (stage 3 and 4 CKD). Mean (SE) number of annual physician visits were 3.51 (0.08), 4.43 (0.18), and 6.53 (0.38) for participants with no CKD, early CKD, and late CKD, respectively. Mean (SE) number of annual hospitalizations were 0.15 (0.01), 0.19 (0.01), and 0.42 (0.03) for participants with no CKD, early CKD, and late CKD, respectively. Participants with late CKD were more likely to have more physician visits (OR 1.81, 95% CI 1.46, 2.23) and have more hospital admissions (OR 2.12, 95% CI 1.66, 2.71) compared with participants with early CKD or no CKD. CONCLUSIONS: In this analysis, late stage CKD was associated with increased HRU, suggesting the need for early identification and treatment of CKD and its associated conditions.

Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis.

Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.

Assessment of the impact of weekly versus monthly erythropoiesis stimulating protein therapy on patients with CKD and their families.

This cross-sectional study measured patient and family member reported treatment and economic burden associated with monthly versus weekly erythropoiesis stimulating protein therapies for anemia in patients with CKD who were not yet on dialysis. The results indicated that compared to a weekly regimen, a monthly regimen saved patients 7 hours and family members 19 hours per month for routine anemia management. The monthly regimen substantially reduced the reported economic and treatment burdens of patient and their family members.

Assessment of time and practice resources required to provide weekly or monthly erythropoiesis-stimulating protein therapy to chronic kidney disease patients in the physician office setting.

BACKGROUND: There is an epidemic of chronic kidney disease (CKD) and a high prevalence of anemia (47%) observed in CKD patients. Little is known about the cost in physician office resources of routine erythropoiesis-stimulating protein (ESP) administration to treat patients with nondialysis CKD. OBJECTIVES: The objectives of this research were (1) to explore the patterns of care in physician offices where nondialysis CKD patients receive routine ESP injections, (2) to examine differences in the monthly resources and related costs incurred by physician offices in treating patients receiving either weekly (QW) or monthly (QM) ESP regimens, and (3) to identify opportunities to minimize the burden of CKD treatment on physician offices. METHODS: An observational, cross-sectional time and motion assessment was performed in 10 community-based outpatient nephrology practices (5 QW and 5 QM practices); each practice had 40 patients on routine ESP therapy for nondialysis CKD. Three observers trained in health care research documented injection-related tasks and time associated with 91 ESP injection procedures (47 QW and 44 QM) from patients. arrival to and departure from the physician office, office personnel follow-up on billing and documentation, and injection-related staff time. Monthly injection times for QM were calculated by summing the time required to perform the tasks associated with administering a single injection of ESP to subjects, as documented by observers. Total monthly per-patient medical practice costs for providing QM ESP injections were calculated, including labor costs (calculated by applying average wage rates of practice staff to time observed for the specific activities performed) and supply costs (based on average list prices found in medical supply catalogs). Monthly injection times and costs for the QW regimen were calculated by summing the same list of activities as for the QM regimen and multiplying by 4.3 (4.3 weeks per month). Nephrology practice personnel completed a questionnaire summarizing practice characteristics and estimated the time required for some of the injection-related activities. The time and cost associated with each task were analyzed using descriptive and comparative statistics (i.e., Fisher.s exact test and t test). RESULTS: On average, patients spent 21 minutes in the clinic for a routine injection visit (QW: 17 minutes, QM: 25 minutes; P=0.053), during which 11 minutes (52%) were spent interacting with clinic staff (QW: 8.9 minutes, QM: 13.4 minutes; P=0.005). In the time spent interacting with staff, 3 minutes (QW: 2.9 minutes, QM: 3.6 minutes; P=0.065) were for dose administration and 8 minutes (QW: 5.3 minutes, QM: 9.8 minutes; P=0.011) were for staff providing various services to the patients, including registering patients on arrival, examining patients (vital signs, weight, blood work), consulting with patients, and scheduling patients. next visits. Each month, clinic staff spent a total visit average of 38 minutes providing anemia-related treatment for each QW injection patient, compared with 13 minutes for each QM injection patient (P <0.001). After patients. departure, clinic staff spent additional time (not quantified) on billing, filing claims, and other administrative responsibilities most of which could not be observed during our 1-day observation. The average total monthly practice cost of providing ESP therapy to a QW patient (17.00 dollars [95% confidence interval (CI), 13.00-27.13]) was more than double that for a QM patient (6.78 dollars [95% CI, 5.34-9.12]); (P=0.004). Differences in visit-related labor costs (QW: 8.34 dollars, QM: 3.43 dollars; P=0.108) and injection supply costs (QW: 4.39 dollars, QM: 1.67 dollars; P <0.001) accounted for the largest portions of the total monthly cost differential between the treatment regimens. QM dosing would require, on average, 83 hours less staff time and 2,044 dollars less estimated cost treating 200 patients per month compared with weekly administration per clinic. CONCLUSIONS: Administering routine ESP injections to nondialysis CKD patients for anemia using a QM regimen results in substantial time and cost savings compared with a QW therapy regimen. Managing patients on less frequent ESP dosing schedules may alleviate medical practice burden by reducing the staff time and supplies related to providing injections in the office.

Coronary Artery Disease Is a Predictor of Progression to Dialysis in Patients With Chronic Kidney Disease, Type 2 Diabetes Mellitus, and Anemia: An Analysis of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BACKGROUND: Although clear evidence shows that chronic kidney disease is a predictor of cardiovascular events, death, and accelerated coronary artery disease (CAD) progression, it remains unknown whether CAD is a predictor of progression of chronic kidney disease to end-stage renal disease. We sought to assess whether CAD adds prognostic information to established predictors of progression to dialysis in patients with chronic kidney disease, diabetes, and anemia. METHODS AND RESULTS: Using the previously described Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) population, we compared baseline characteristics of patients with and without CAD. Cox proportional hazards models were used to assess the association between CAD and the outcomes of end-stage renal disease and the composite of death or end-stage renal disease. Of the 4038 patients, 1791 had a history of known CAD. These patients were older (mean age 70 versus 65 years, P<0.001) and more likely to have other cardiovascular disease. CAD patients were less likely to have marked proteinuria (29% versus 39%, P<0.001), but there was no significant difference in estimated glomerular filtration rate between the 2 groups. After adjusting for age, sex, race, estimated glomerular filtration rate, proteinuria, treatment group, and 14 other renal risk factors, patients with CAD were significantly more likely to progress to end-stage renal disease (adjusted hazard ratio 1.20 [95% CI 1.01-1.42], P=0.04) and to have the composite of death or end-stage renal disease (adjusted hazard ratio 1.15 [95% CI 1.01-1.30], P=0.03). CONCLUSIONS: In patients with chronic kidney disease, diabetes, and anemia, a history of CAD is an independent predictor of progression to dialysis. In patients with diabetic nephropathy, a history of CAD contributes important prognostic information to traditional risk factors for worsening renal disease.

Prevalence and severity of chronic kidney disease and anemia in the nursing home population.

OBJECTIVES: Chronic kidney disease (CKD) is an emerging health concern and may have important implications for the management of older people with many other chronic conditions, such as the nursing home (NH) resident population. This study was designed to describe the prevalence of CKD and associated comorbidities in a representative sample of NH residents. DESIGN: Cross-sectional descriptive study as a component of a prospective observational study of CKD and anemia in the NH population. SETTING: Eighty-two geographically representative NHs in the United States. PARTICIPANTS: Participants were 794 NH residents who had complete baseline data collected. MEASUREMENTS: Residents for whom consent was obtained underwent a record review focused on identifying a predefined set of comorbid conditions, clinical assessment, and blood and urine collections. Stage of CKD was based on estimated GFR (eGFR) using the MDRD equation: no CKD (eGFR > 60 mL/min/1.73 m(2)), Stage 3a (45-59), Stage 3b (30-44), and Stage 4/5 (< 30). RESULTS: Consent was obtained from 847 of 1626 residents screened; 32 were ineligible and 21 dropped out of the study; complete data were available for 794 residents. CKD was present in approximately 50% of residents; of these residents with CKD, 47.6% were stage 3a, 39.27% stage 3b, and 13.2% stage 4/5. Fifty percent of the population had anemia, and anemia was more common in those with CKD. The average number of comorbid conditions in the population was 5.3 (SD 2.2); the proportion of patients with multiple comorbid conditions, especially cardiovascular conditions, increased with increasing stage of CKD. Among those without CKD, 57% had 5 or more comorbidities in comparison to 87% of those with stage 4/5 CKD. CONCLUSIONS: In this representative sample of 794 US NH residents, 50% had clinical evidence of CKD. Patients with CKD, particularly those at later stages, were more likely to have cardiovascular comorbidities and anemia. The co-occurrence of these conditions in institutionalized populations may have important implications for the clinical management of this patient population, particularly as it relates to the potential for further renal complications.

Every-other-week darbepoetin alfa in the correction and maintenance of haemoglobin levels in elderly patients with chronic kidney disease: post hoc subanalysis of data from two clinical trials.

BACKGROUND: Anaemia is a common complication of chronic kidney disease (CKD) and is associated with increased rates of mortality and diminished quality of life in patients with CKD. Although extended dosing with darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), has been shown to be effective in maintaining haemoglobin (Hb) levels in CKD patients, little information is published on the use of darbepoetin alfa in the correction and maintenance of Hb levels in elderly CKD patients naive to ESA therapy. OBJECTIVE: This post hoc subanalysis of data from two clinical trials was conducted to investigate the efficacy and safety profile of de novo every-other-week (q2w) darbepoetin alfa in elderly patients with CKD-associated anaemia (not on dialysis), as compared with that of a younger (aged <65 years) patient cohort. METHODS: This analysis was based on data obtained from two open-label, single-arm, multicentre studies of similar design. Patients were aged >or=18 years and naive to previous ESA therapy. Darbepoetin alfa administration was initiated at 0.75 microg/kg and titrated according to individual patient requirements to achieve and maintain Hb levels between 11.0 and 13.0 g/dL. The proportion of patients who achieved the primary endpoint, Hb >or=11.0 g/dL (study 1), and an Hb level between 11.0 and 13.0 g/dL (study 2) at weeks 4, 8 and 12 weeks and at the end of the study were determined. The results of this subanalysis were stratified by age (<65, 65-74 and >or=75 years). RESULTS: A total of 203 patients were enrolled in the two studies; 60% were female, 84 (41%) were aged <65 years, 57 (28%) were aged 65-74 years and 62 (31%) were aged >or=75 years. The proportion of patients who achieved Hb levels of >or=11.0 g/dL in study 1 and 11.0-13.0 g/dL in study 2 at week 20 were 93%, 96% and 92%, respectively, for the three age groups. Weight-adjusted q2w darbepoetin alfa doses were similar between the age groups and stable throughout the study period. The mean (standard deviation) Hb levels at week 21 were 12.0 (1.2), 12.7 (1.1) and 12.6 (1.0) g/dL in subjects aged <65, 65-74 and >or=75 years, respectively. The median (standard error) time to reach the primary endpoint was 5.0 (4.7), 5.0 (5.7) and 5.0 (5.7) weeks for subjects aged <65 years, 65-74 years and >or=75 years, respectively. The safety profiles of q2w darbepoetin alfa in both the older and younger age-groups were consistent with those expected for patients with CKD not receiving dialysis. CONCLUSIONS: The results of this study suggest that ESA-naive subjects aged <65, 65-74 and >or=75 years of age with CKD (not receiving dialysis) who received q2w darbepoetin alfa were able to achieve and maintain Hb levels at 11.0-13.0 g/dL. The de novo q2w treatment regimen with darbepoetin alfa described in the present report may help optimize anaemia management in CKD-associated anaemia patients, including those in the older adult population.

Association of anemia correction with health related quality of life in patients not on dialysis.

OBJECTIVE: This was an open-label study to asses the association of changes in hemoglobin with changes in health related quality of life (HRQOL) in patients treated with darbepoetin alfa. METHODS: Originally, 81 chronic kidney disease (CKD) patients not on dialysis and naïve to erythropoiesis stimulating agents (ESA) were randomly assigned into two open-label groups (3 : 1). As a majority of control group patients opted out of control status, this study reports on the single arm study analysis that was performed on the 48 patients who received the drug through week 16. Sixty-two patients received once-weekly darbepoetin alfa in addition to conservative management for CKD. Instruments that measured general (SF-36, FACTanemia, FACT-fatigue, ADL and IADL) and disease specific (KDQOL) HRQOL domains were administered at baseline and after 8, 16, and 24 weeks. RESULTS: Compared to baseline values, mean HRQOL subscales were significantly improved in the treatment group at 16 weeks (p < 0.05 for SF-36 physical function; p < 0.001 for SF-36 vitality, FACT anemia and FACT fatigue scales). At week 16, the SF-36 mean increase for 48 treatment patients in the Vitality Subscale Score was 14.9 (SD 3.2) and the mean increase in the KDQOL Burden of Kidney Disease Subscale was 5.5 (SD 3.3). Multivariate regression analysis demonstrated a statistically significant association (p < 0.05) between hemoglobin levels and higher HRQOL scores on several physical function, energy and fatigue scales. CONCLUSION: Improvements in hemoglobin in CKD patients not on dialysis were associated with statistically significant (p < 0.05), clinically meaningful (> 5 points) HRQOL improvements on scales measuring physical activity, vitality and fatigue. Our study did not show an association between increased hemoglobin levels and other aspects of HRQOL, such as those relating to emotional status, sexual activity or cognition. The interpretation of our results is limited by the lack of a control arm to assess whether conservative therapy for CKD, in the absence of ESA administration, would have a comparable effect on patients' HRQOL scores. Further research needs to examine whether other aspects of HRQOL improve with anemia treatment, in the same way as those aspects of HRQOL more closely related to physical activity and fatigue.