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1.
N Engl J Med ; 385(25): 2325-2335, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1575626

ABSTRACT

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).


Subject(s)
Anemia/drug therapy , Barbiturates/therapeutic use , Darbepoetin alfa/therapeutic use , Epoetin Alfa/therapeutic use , Glycine/analogs & derivatives , Hematinics/therapeutic use , Renal Dialysis , Renal Insufficiency, Chronic/complications , Aged , Anemia/etiology , Barbiturates/adverse effects , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Darbepoetin alfa/adverse effects , Epoetin Alfa/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Hematinics/adverse effects , Hemoglobins/analysis , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Intention to Treat Analysis , Male , Middle Aged , Myocardial Infarction/epidemiology , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/therapy , Stroke/epidemiology
2.
N Engl J Med ; 385(25): 2313-2324, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1575625

ABSTRACT

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).


Subject(s)
Anemia/drug therapy , Barbiturates/therapeutic use , Darbepoetin alfa/therapeutic use , Glycine/analogs & derivatives , Hematinics/therapeutic use , Renal Insufficiency, Chronic/complications , Aged , Anemia/etiology , Barbiturates/adverse effects , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Darbepoetin alfa/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Hematinics/adverse effects , Hemoglobins/analysis , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Intention to Treat Analysis , Male , Middle Aged , Myocardial Infarction/epidemiology , Renal Insufficiency, Chronic/blood , Stroke/epidemiology
3.
J Am Soc Nephrol ; 32(1): 115-126, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496665

ABSTRACT

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.


Subject(s)
Biomarkers/blood , Diabetic Nephropathies/genetics , Kidney Failure, Chronic/genetics , Renal Insufficiency, Chronic/genetics , Adult , Aged , Chemokine CCL2/blood , Chitinase-3-Like Protein 1/blood , Cohort Studies , Diabetic Nephropathies/blood , Disease Progression , Female , Glomerular Filtration Rate , Hepatitis A Virus Cellular Receptor 1/blood , Humans , Kidney Failure, Chronic/blood , Male , Middle Aged , Phenotype , Prevalence , Receptors, Tumor Necrosis Factor, Type I/blood , Receptors, Tumor Necrosis Factor, Type II/blood , Receptors, Urokinase Plasminogen Activator/blood , Renal Insufficiency, Chronic/blood , Risk , Young Adult
4.
J Am Soc Nephrol ; 32(3): 639-653, 2021 03.
Article in English | MEDLINE | ID: covidwho-1496657

ABSTRACT

BACKGROUND: CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes. METHODS: We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death. RESULTS: The algorithm revealed three unique CKD subgroups that best represented patients' baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 (n=1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 (n=1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 (n=395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged. CONCLUSIONS: Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.


Subject(s)
Renal Insufficiency, Chronic/classification , Adult , Aged , Algorithms , Bone Density , Cohort Studies , Disease Progression , Female , Heart Function Tests , Humans , Kaplan-Meier Estimate , Kidney Function Tests , Male , Middle Aged , Prognosis , Prospective Studies , Renal Insufficiency, Chronic/physiopathology , Risk Factors , Unsupervised Machine Learning , Young Adult
5.
PLoS One ; 16(6): e0252679, 2021.
Article in English | MEDLINE | ID: covidwho-1259245

ABSTRACT

INTRODUCTION: End-stage kidney disease (ESKD) patients are at a high risk for Coronavirus Disease 2019 (COVID-19). In this study, we compared characteristics and outcomes of ESKD and non-ESKD patients admitted with COVID-19 to a large safety-net hospital. METHODS: We evaluated 759 adults (45 with ESKD) hospitalized with COVID-19 in Spring of 2020. We examined clinical characteristics, laboratory measures and clinical outcomes. Logistic regression analyses were performed to investigate the associations between ESKD status and outcomes. RESULTS: 73% of ESKD and 47% of non-ESKD patients identified as Black (p = 0.002). ESKD patients were older and had higher rates of comorbidities. Admission ferritin was approximately 6-fold higher in ESKD patients. During hospitalization, the rise in white blood cell count, lactate dehydrogenase, ferritin and C-reactive protein, and the decrease in platelet count and serum albumin were all significantly greater in ESKD patients. The in-hospital mortality was higher for ESKD [18% vs. 10%; multivariable adjusted odds ratio 1.5 (95% CI, 0.48-4.70)], but this did not reach statistical significance. CONCLUSIONS: Among hospitalized COVID-19 patients, ESKD patients had more co-morbidities and more robust inflammatory response than non-ESKD patients. The odds ratio point estimate for death was higher in ESKD patients, but the difference did not reach statistical significance.


Subject(s)
COVID-19/mortality , Hospital Mortality , Hospitals, Urban , Kidney Failure, Chronic/mortality , SARS-CoV-2 , Safety , Adult , Aged , Boston/epidemiology , COVID-19/blood , Comorbidity , Female , Humans , Kidney Failure, Chronic/blood , Male , Middle Aged , Retrospective Studies
6.
Kidney Med ; 2020 Oct 14.
Article in English | MEDLINE | ID: covidwho-857254

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic and a public health emergency. The overwhelming rise in the number of cases has brought significant challenges to healthcare systems worldwide. Patients with end-stage kidney disease (ESKD) are highly vulnerable with the multiple comorbidities that make them susceptible to adverse outcomes with COVID-19. Over 2 million people worldwide receive maintenance hemodialysis (HD) at outpatient centers. Effectively preventing the spread of infection among HD centers, healthcare personnel, and patients is essential to ensure the continued delivery of dialysis to ESKD patients. This article discusses dialysis patients' care during COVID-19, addressing measures for patient and health care personnel protection and care of dialysis patients with suspected or confirmed COVID-19.

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