Reshma Kewalramani

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.)

Pharmacoepidemiology of Anemia in Kidney Transplant Recipients

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.

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.

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.

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.

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 (PROs) 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.

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.

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

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

ABSTRACT 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, FACT-anemia, 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.

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.