Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes

Harvard University, Cambridge, Massachusetts, United States
New England Journal of Medicine (Impact Factor: 55.87). 09/2010; 363(12):1146-55. DOI: 10.1056/NEJMoa1005109
Source: PubMed


Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response.
We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug.
Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78).
A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; number, NCT00093015.)

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Available from: Peter Ivanovich, Feb 26, 2014
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    • "Diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD), [DCC] are significant causes of morbidity and excess mortality and with an alarmingly increasing global trend. Together, they constitute the DCC-disease complex that accounts for major human suffering and already more than 15% of the economic burden on all Healthcare systems (1, 2) Consequently, there are ever increasing academic, industrial, and societal investment needs in combating this worsening epidemic. "
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    ABSTRACT: Diabetes represents a major threat to public health and the number of patients is increasing alarmingly in the global scale. Particularly, the diabetic kidney disease (nephropathy, DN) together with its cardiovascular complications cause immense human suffering, highly increased risk of premature deaths, and lead to huge societal costs. DN is first detected when protein appears in urine (microalbuminuria). As in other persisting proteinuric diseases (like vasculitis) it heralds irreversible damage of kidney functions up to non-functional (end-stage) kidney and ultimately calls for kidney replacement therapy (dialysis or kidney transplantation). While remarkable progress has been made in understanding the genetic and molecular factors associating with chronic kidney diseases, breakthroughs are still missing to provide comprehensive understanding of events and mechanisms associated. Non-invasive diagnostic tools for early diagnostics of kidney damage are badly needed. Exosomes - small vesicular structures present in urine are released by all cell types along kidney structures to present with distinct surface assembly. Furthermore, exosomes carry a load of special proteins and nucleic acids. This "cargo" faithfully reflects the physiological state of their respective cells of origin and appears to serve as a new pathway for downstream signaling to target cells. Accordingly, exosome vesicles are emerging as a valuable source for disease stage-specific information and as fingerprints of disease progression. Unfortunately, technical issues of exosome isolation are challenging and, thus, their full potential remains untapped. Here, we review the molecular basis of exosome secretion as well as their use to reveal events along the nephron. In addition to novel molecular information, the new methods provide the needed accurate, personalized, non-invasive, and inexpensive future diagnostics.
    Full-text · Article · Sep 2014 · Frontiers in Endocrinology
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    • "Thus the inability to achieve a proper hematopoietic response seems to be the best marker of worse prognosis. Secondary analyses of anemia correction trials also confirm this association between ESA resistance and mortality [12,42], but the causal pathway is not yet fully understood. "
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    ABSTRACT: Responsiveness to erythropoiesis-stimulating agents (ESAs) varies widely among dialysis patients. ESA resistance has been associated with mortality in hemodialysis (HD) patients, but in peritoneal dialysis (PD) patients data is limited. Therefore we assessed the relation between ESA resistance in both HD and PD patients. NECOSAD is a Dutch multi-center prospective cohort study of incident dialysis patients who started dialysis between January 1997 and January 2007. ESA resistance was defined as hemoglobin level < 11 g/dL with an above median ESA dose (i.e. 8,000 units/week in HD and 4,000 units/week in PD patients). Unadjusted and adjusted Cox regression analysis for all-cause 5-year mortality was performed for HD and PD patients separately. 1013 HD and 461 PD patients were included in the analysis. ESA resistant HD patients had an adjusted hazard ratio of 1.37 (95% CI 1.04-1.80) and ESA resistant PD patients had an adjusted hazard ratio of 2.41 (1.27-4.57) as compared to patients with a good response. ESA resistance, as defined by categories of ESA and Hb, is associated with increased mortality in both HD and PD patients. The effect of ESA resistance, ESA dose and hemoglobin are closely related and the exact mechanism remains unclear. Our results strengthen the need to investigate and treat causes of ESA resistance not only in HD, but also in PD patients.
    Full-text · Article · Sep 2013 · BMC Nephrology
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    • "According to this arbitrary definition, more than 90–95% of HD patients treated with an ESA respond to the therapy with a sufficient rise in the hemoglobin value [5], whereas 5–10% do not adequately respond to the therapy. Of note, resistance to ESAs has consistently been shown to be associated with an increased risk of death and cardiovascular events in CKD patients [6-8]. In the recent TREAT trial, diabetic patients with CKD were at highest risk of mortality when they had a poor response to the initial two doses of darbepoietin alfa [6]. "
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    ABSTRACT: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients. A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers. In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance. Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies. Clinical trial registration The study was registered at the German medical authority (BfArM; registration number 401 3206). The sponsor protocol ID and clinical trial unique identified number was CT-981-423-239. The results of the study are published and available at
    Full-text · Article · Mar 2013 · BMC Nephrology
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