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Garofalo C, Borrelli S, Liberti ME, Chiodini P, Peccarino L, Pennino L, Polese L, De Gregorio I, Scognamiglio M, Ruotolo C, Provenzano M, Conte G, Minutolo R, De Nicola L. Secular Trend in GFR Decline in Non-Dialysis CKD Based on Observational Data From Standard of Care Arms of Trials. Am J Kidney Dis 2024; 83:435-444.e1. [PMID: 37956953 DOI: 10.1053/j.ajkd.2023.09.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 08/24/2023] [Accepted: 09/07/2023] [Indexed: 11/21/2023]
Abstract
RATIONALE & OBJECTIVE The standard of care (SoC) group of randomized controlled trials (RCTs) is a useful setting to explore the secular trends in kidney disease progression because implementation of best clinical practices is pursued for all patients enrolled in trials. This meta-analysis evaluated the secular trend in the change of glomerular filtration rate (GFR) decline in the SoC arm of RCTs in chronic kidney disease (CKD) published in the last 30 years. STUDY DESIGN Systematic review and meta-analysis of the SoC arms of RCTs analyzed as an observational study. SETTING & STUDY POPULATIONS Adult patients with CKD enrolled in the SoC arm of RCTs. SELECTION CRITERIA FOR STUDIES Phase 3 RCTs evaluating GFR decline as an outcome in SoC arms. DATA EXTRACTION Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH The mean of GFR declines extracted in the SoC arm of selected RCTs were pooled by using a random effects model. Meta-regression analyses were performed to identify factors that may explain heterogeneity. RESULTS The SoC arms from 92 RCTs were included in the meta-analysis with a total of 32,202 patients. The overall mean GFR decline was-4.00 (95% CI, -4.55 to-3.44) mL/min/1.73m2 per year in the SoC arms with a high level of heterogeneity (I2, 98.4% [95% CI, 98.2-98.5], P<0.001). Meta-regression analysis showed an association between publication year (β estimate, 0.09 [95% CI, 0.032-0.148], P=0.003) and reduction in GFR over time. When evaluating publication decade categorically, GFR decline was-5.44 (95% CI, -7.15 to-3.73), -3.92 (95% CI, -4.82 to-3.02), and -3.20 (95% CI, -3.75 to -2.64) mL/min/1.73m2 per year during 1991-2000, 2001-2010, and 2011-2023, respectively. Using meta-regression, the heterogeneity of GFR decline was mainly explained by age and proteinuria. LIMITATIONS Different methods assessing GFR in selected trials and observational design of the study. CONCLUSIONS In the last 3 decades, GFR decline has decreased over time in patients enrolled in RCTs who received the standard of care. TRIAL REGISTRATION Registered at PROSPERO with record number CRD42022357704. PLAIN-LANGUAGE SUMMARY This study evaluated the secular trend in the change in glomerular filtration rate (GFR) decline in the placebo arms of randomized controlled trials (RCTs) that were studying approaches to protect the kidneys in the setting of chronic kidney disease. The placebo groups of RCTs are useful for examining whether the rate of progression of kidney disease has changed over time. We found an improvement in the slope of change in GFR over time. These findings suggest that adherence to standards of kidney care as implemented in clinical trials may be associated with improved clinical outcomes, and these data may inform the design of future RCTs in nephrology.
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Affiliation(s)
- Carlo Garofalo
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy.
| | - Silvio Borrelli
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Maria Elena Liberti
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Paolo Chiodini
- Medical Statistics Unit, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Laura Peccarino
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Luigi Pennino
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Lucio Polese
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Ilaria De Gregorio
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | | | - Chiara Ruotolo
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Michele Provenzano
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Giuseppe Conte
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Roberto Minutolo
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Luca De Nicola
- Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy
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Habas E, Al Adab A, Arryes M, Alfitori G, Farfar K, Habas AM, Akbar RA, Rayani A, Habas E, Elzouki A. Anemia and Hypoxia Impact on Chronic Kidney Disease Onset and Progression: Review and Updates. Cureus 2023; 15:e46737. [PMID: 38022248 PMCID: PMC10631488 DOI: 10.7759/cureus.46737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Chronic kidney disease (CKD) is caused by hypoxia in the renal tissue, leading to inflammation and increased migration of pathogenic cells. Studies showed that leukocytes directly sense hypoxia and respond by initiating gene transcription, encoding the 2-integrin adhesion molecules. Moreover, other mechanisms participate in hypoxia, including anemia. CKD-associated anemia is common, which induces and worsens hypoxia, contributing to CKD progression. Anemia correction can slow CKD progression, but it should be cautiously approached. In this comprehensive review, the underlying pathophysiology mechanisms and the impact of renal tissue hypoxia and anemia in CKD onset and progression will be reviewed and discussed in detail. Searching for the latest updates in PubMed Central, Medline, PubMed database, Google Scholar, and Google search engines were conducted for original studies, including cross-sectional studies, cohort studies, clinical trials, and review articles using different keywords, phrases, and texts such as "CKD progression, anemia in CKD, CKD, anemia effect on CKD progression, anemia effect on CKD progression, and hypoxia and CKD progression". Kidney tissue hypoxia and anemia have an impact on CKD onset and progression. Hypoxia causes nephron cell death, enhancing fibrosis by increasing interstitium protein deposition, inflammatory cell activation, and apoptosis. Severe anemia correction improves life quality and may delay CKD progression. Detection and avoidance of the risk factors of hypoxia prevent recurrent acute kidney injury (AKI) and reduce the CKD rate. A better understanding of kidney hypoxia would prevent AKI and CKD and lead to new therapeutic strategies.
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Affiliation(s)
| | - Aisha Al Adab
- Internal Medicine, Hamad General Hospital, Doha, QAT
| | - Mehdi Arryes
- Internal Medicine, Hamad General Hospital, Doha, QAT
| | | | | | - Ala M Habas
- Internal Medicine, Tripoli University, Tripoli, LBY
| | - Raza A Akbar
- Internal Medicine, Hamad General Hospital, Doha, QAT
| | - Amnna Rayani
- Hemat-oncology Department, Pediatric Tripoli Hospital, Tripoli University, Tripoli, LBY
| | - Eshrak Habas
- Internal Medicine, Tripoli University, Tripoli, LBY
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Chung EY, Palmer SC, Saglimbene VM, Craig JC, Tonelli M, Strippoli GF. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev 2023; 2:CD010590. [PMID: 36791280 PMCID: PMC9924302 DOI: 10.1002/14651858.cd010590.pub3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
BACKGROUND Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014. OBJECTIVES To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. DATA COLLECTION AND ANALYSIS Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data. AUTHORS' CONCLUSIONS: The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.
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Affiliation(s)
- Edmund Ym Chung
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Valeria M Saglimbene
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Marcello Tonelli
- Department of Medicine, University of Calgary, Calgary, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Giovanni Fm Strippoli
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Maki KC, Wilcox ML, Dicklin MR, Kakkar R, Davidson MH. Left ventricular mass regression, all-cause and cardiovascular mortality in chronic kidney disease: a meta-analysis. BMC Nephrol 2022; 23:34. [PMID: 35034619 PMCID: PMC8761349 DOI: 10.1186/s12882-022-02666-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 01/03/2022] [Indexed: 12/22/2022] Open
Abstract
Background Cardiovascular disease is an important driver of the increased mortality associated with chronic kidney disease (CKD). Higher left ventricular mass (LVM) predicts increased risk of adverse cardiovascular outcomes and total mortality, but previous reviews have shown no clear association between intervention-induced LVM change and all-cause or cardiovascular mortality in CKD. Methods The primary objective of this meta-analysis was to investigate whether treatment-induced reductions in LVM over periods ≥12 months were associated with all-cause mortality in patients with CKD. Cardiovascular mortality was investigated as a secondary outcome. Measures of association in the form of relative risks (RRs) with associated variability and precision (95% confidence intervals [CIs]) were extracted directly from each study, when reported, or were calculated based on the published data, if possible, and pooled RR estimates were determined. Results The meta-analysis included 42 trials with duration ≥12 months: 6 of erythropoietin stimulating agents treating to higher vs. lower hemoglobin targets, 10 of renin-angiotensin-aldosterone system inhibitors vs. placebo or another blood pressure lowering agent, 14 of modified hemodialysis regimens, and 12 of other types of interventions. All-cause mortality was reported in 121/2584 (4.86%) subjects in intervention groups and 168/2606 (6.45%) subjects in control groups. The pooled RR estimate of the 27 trials ≥12 months with ≥1 event in ≥1 group was 0.72 (95% CI 0.57 to 0.90, p = 0.005), with little heterogeneity across studies. Directionalities of the associations in intervention subgroups were the same. Sensitivity analyses of ≥6 months (34 trials), ≥9 months (29 trials), and >12 months (10 trials), and including studies with no events in either group, demonstrated similar risk reductions to the primary analysis. The point estimate for cardiovascular mortality was similar to all-cause mortality, but not statistically significant: RR 0.67, 95% CI 0.39 to 1.16. Conclusions These results suggest that LVM regression may be a useful surrogate marker for benefits of interventions intended to reduce mortality risk in patients with CKD. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-022-02666-1.
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Affiliation(s)
- Kevin C Maki
- Department of Applied Health Science, Indiana University School of Public Health, 1025 E 7th St #111, Bloomington, IN, 47405, USA. .,Midwest Biomedical Research, Addison, IL, USA.
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6
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Maruyama Y, Kanda E, Kikuchi K, Abe M, Masakane I, Yokoo T, Nitta K. Association between anemia and mortality in hemodialysis patients is modified by the presence of diabetes. J Nephrol 2021; 34:781-790. [PMID: 33555578 DOI: 10.1007/s40620-020-00879-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/20/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND The prevalence and severity of anemia differ between diabetic and non-diabetic patients. We investigated whether the effect of hemoglobin (Hb) on patient outcome was affected by the presence or absence of diabetes among Japanese patients receiving chronic hemodialysis (HD). METHODS We enrolled 149,308 patients from a nationwide dialysis registry in Japan at the end of 2012 (mean age, 67.6 ± 12.3 years; male, 61.7%; diabetes, 43.5%; median dialysis duration, 65 months) who underwent three HD sessions weekly. One-year all-cause and cardiovascular (CV) mortality were assessed using Cox regression analysis and competing-risks regression analysis. We used multiple imputation to deal with missing covariate data. RESULTS Baseline Hb and serum ferritin levels were independently associated with all-cause and CV mortality. In non-diabetic patients, a significantly higher risk for all-cause mortality compared to the reference group (10 to 11 g/dL) was observed in patients with Hb < 8 g/dL (hazard ratio (HR): 1.266; 95% confidence interval (CI) 1.097-1.460) and 8 to 9 g/dL(HR: 1.153; 95% CI 1.030-1.290). On the other hand, diabetic HD patients in the same Hb category group did not have increased risk of all-cause mortality. CONCLUSIONS We found that non-diabetic HD patients had an increased risk of all-cause mortality if they had lower Hb levels, whereas the effect of Hb levels on mortality was attenuated in diabetic HD patients. These data suggest that the association between Hb levels and mortality rate could be different between diabetic and non-diabetic HD patients.
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Affiliation(s)
- Yukio Maruyama
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi Minato-ku, Tokyo, 1058461, Japan. .,Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.
| | - Eiichiro Kanda
- Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.,Medical Science, Kawasaki Medical School, Okayama, Japan
| | - Kan Kikuchi
- Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.,Shimoochiai Clinic, Tokyo, Japan
| | - Masanori Abe
- Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.,Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Ikuto Masakane
- Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.,Department Nephrology, Honcho Yabuki Clinic, Yamagata, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi Minato-ku, Tokyo, 1058461, Japan
| | - Kosaku Nitta
- Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.,Fourth Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
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Hanna RM, Streja E, Kalantar-Zadeh K. Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin. Adv Ther 2021; 38:52-75. [PMID: 33123967 PMCID: PMC7854472 DOI: 10.1007/s12325-020-01524-6] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/03/2020] [Indexed: 02/08/2023]
Abstract
Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.
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Affiliation(s)
- Ramy M Hanna
- Division of Nephrology, Hypertension and Kidney Transplantation, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California, Irvine School of Medicine, Orange, CA, USA
| | - Elani Streja
- Division of Nephrology and Hypertension, University of California, Irvine School of Medicine, Orange, CA, USA
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology and Hypertension, University of California, Irvine School of Medicine, Orange, CA, USA.
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Guedes M, Guetter CR, Erbano LHO, Palone AG, Zee J, Robinson BM, Pisoni R, de Moraes TP, Pecoits-Filho R, Baena CP. Physical health-related quality of life at higher achieved hemoglobin levels among chronic kidney disease patients: a systematic review and meta-analysis. BMC Nephrol 2020; 21:259. [PMID: 32641153 PMCID: PMC7346455 DOI: 10.1186/s12882-020-01912-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 06/26/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The impact of anemia treatment with erythropoietin stimulating agents (ESA) on health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients is controversial, particularly regarding optimal hemoglobin (Hb) target ranges. METHODS We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCT) with ESA to estimate the effect of different achieved Hb values on physical HRQOL and functionality. We searched PubMed, EMBASE, CENTRAL, PEDro, PsycINFO and Web of Science databases, until May 2020. Two authors independently extracted data from studies. We included observational and RCTs that enrolled CKD patients undergoing anemia treatment with ESA with different achieved Hb levels among groups. We excluded studies with achieved Hb < 9 g/dL. For the meta-analysis, we included RCTs with control groups achieving Hb 10-11.5 g/dL and active groups with Hb > 11.5 g/dL. We analyzed the standardized mean difference (SMD) between groups for physical HRQOL. RESULTS Among 8496 studies, fifteen RCTs and five observational studies were included for the systematic review. We performed the meta-analysis in a subset of eleven eligible RCTs. For physical role and physical function, SMDs were 0.0875 [95% CI: - 0.0025 - 0.178] and 0.08 [95% CI: - 0.03 - 0.19], respectively. For fatigue, SMD was 0.16 [95% CI: 0.09-0.24]. Subgroup analysis showed that trials with greater achieved Hb had greater pooled effects sizes - 0.21 [95% CI: 0.07-0.36] for Hb > 13 g/dL vs. 0.09 [95% CI: 0.02-0.16] for Hb 11.5-13 g/dL. Proportion of older and long-term diabetic patients across studies were associated with lower effect sizes. CONCLUSION Achieved hemoglobin higher than currently recommended targets may be associated with small but potentially clinically significant improvement in fatigue, but not in physical role or physical function. Younger and non-diabetic patients may experience more pronounced benefits of higher Hb levels after treatment with ESAs.
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Affiliation(s)
- Murilo Guedes
- Pontifícia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR, 80215-901, Brazil.
| | | | - Lucas H O Erbano
- Pontifícia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR, 80215-901, Brazil
| | - Andre G Palone
- Pontifícia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR, 80215-901, Brazil
| | - Jarcy Zee
- Arbor Research Collaborative for Health, Ann Arbor, MI, USA
| | | | - Ronald Pisoni
- Arbor Research Collaborative for Health, Ann Arbor, MI, USA
| | - Thyago Proença de Moraes
- Pontifícia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR, 80215-901, Brazil
| | - Roberto Pecoits-Filho
- Pontifícia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR, 80215-901, Brazil
- Arbor Research Collaborative for Health, Ann Arbor, MI, USA
| | - Cristina P Baena
- Pontifícia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR, 80215-901, Brazil
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Tsujita M, Kosugi T, Goto N, Futamura K, Nishihira M, Okada M, Hiramitsu T, Narumi S, Uchida K, Takeda A, Morozumi K, Maruyama S, Watarai Y. The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial. Nephrol Dial Transplant 2020; 34:1409-1416. [PMID: 30561729 PMCID: PMC6680099 DOI: 10.1093/ndt/gfy365] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 10/19/2018] [Indexed: 01/14/2023] Open
Abstract
Background Posttransplant anemia may be a major determinant of chronic allograft nephropathy. However, the impact of correcting anemia on graft function remains controversial. Methods A 3-year follow-up of an open-label, multicenter, randomized controlled trial involving kidney transplantation recipients examined whether sustained maintenance of target hemoglobin (Hb) concentrations at a high level (12.5–13.5 g/dL, n = 64) with either darbepoetin alfa or epoetin beta pegol would slow the graft function decline rate as the primary efficacy endpoint, compared with maintenance of a low Hb concentration (10.5–11.5 g/dL, n = 63). Results The mean blood pressures in the two groups were well controlled throughout the study. In the high Hb group, mean Hb concentrations increased to >12 g/dL at 3 months, reaching the target range at 18 months. At the end of this study (36 months), the mean Hb concentration was 12.8 ± 0.7 g/dL in the high Hb group and 11.5 ± 1.2 g/dL in the low Hb group. The decline rate of the estimated glomerular filtration (eGFR) rate was considerably greater in the low Hb group (ΔeGFR, −5.1 ± 9.5 mL/min/1.73 m2) than in the high Hb group (−1.0 ± 8.4 mL/min/1.73 m2) (P = 0.02). Of note, only a few high Hb patients developed cardiovascular events and returned to hemodialysis, but the low Hb patients did not. Conclusion This prospective study suggests that correcting anemia to the target Hb level range (12.5–13.5 g/dL) slows renal function deterioration by >3 years in the chronic phase of allograft nephropathy.
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Affiliation(s)
- Makoto Tsujita
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.,Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norihiko Goto
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kenta Futamura
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Morikuni Nishihira
- Department of Renal Transplantation, Masuko Memorial Hospital, Nagoya, Japan
| | - Manabu Okada
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Takahisa Hiramitsu
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Shunji Narumi
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kazuharu Uchida
- Department of Renal Transplantation, Masuko Memorial Hospital, Nagoya, Japan
| | - Asami Takeda
- Department of Nephrology, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kunio Morozumi
- Department of Renal Transplantation, Masuko Memorial Hospital, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiko Watarai
- Department of Transplant Nephrology and Surgery, Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
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10
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Abstract
Anemia is the major complication resulting from chronic kidney disease (CKD) and also a risk factor for cardiovascular events and a poor quality of life (QoL). Diabetic kidney disease (DKD) is the major cause of CKD. Initially, insulin resistance has been reported to increase erythropoiesis, but it might be a minor issue. DKD-related anemia developed earlier and was more severe than non-DKD-related anemia based on more complicated mechanisms, including greater bleeding tendency associated with antiplatelet effect, less O2 sensing due to autonomic neuropathy or renin-angiotensin-aldosterone system inhibitor use, inhibitory effect of inflammatory cytokines, urinary loss of erythropoietin (EPO), and poor response to EPO. In DKD patients, prompt correction of anemia allows for a better cardiovascular outcome and QoL, which are similar to the promising effect of anemia correction in CKD patients. However, current evidence recommended that the avoidance of a high or normalized hemoglobin (Hb) level has been suggested in the treatment of anemia in DKD patients. Despite that EPO has a pleotropic effect on renal protection from animal studies, the renal benefit was less evident in CKD and DKD patients. Recently, the antidiabetic agent, sodium glucose cotransporter-2 inhibitors (SGLT2i), has been reported to exhibit the renal benefits due to the tubulo-glomerular feedback in addition to sugar control. It may also be due to less renal ischemic through higher EPO levels, followed by higher Hb levels. More studies are needed to clarify the link between the renal benefit of SGLT2i and EPO production.
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Affiliation(s)
- Shang-Feng Tsai
- Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
- Department of Life Science, Tunghai University, Taichung, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Der-Cherng Tarng
- Institutes of Physiology and Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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11
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Okumi M, Okabe Y, Unagami K, Kakuta Y, Iizuka J, Takagi T, Shirakawa H, Shimizu T, Omoto K, Ishida H, Nakamura M, Tanabe K. The interaction between post-transplant anemia and allograft function in kidney transplantation: The Japan Academic Consortium of Kidney Transplantation-II study. Clin Exp Nephrol 2019; 23:1066-1075. [PMID: 31020441 DOI: 10.1007/s10157-019-01737-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 04/09/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND The interaction between post-transplant anemia (PTA) and allograft function in kidney transplantation has not been evaluated directly. PTA, defined by WHO/AST criteria, was investigated in 1307 adult kidney transplant recipients between 2000 and 2015 (median follow-up, 7 years). METHODS We investigated the impact of hemoglobin (Hb) on graft failure (non-censored for death) and their interactions, time-dependent Cox model, and subgroup analysis were used. RESULTS PTA prevalence was 43.6% at 7 years and varied according to allograft function, recipient sex, and follow-up period. Decreased Hb considering the time-varying effect was associated with an increased risk of graft failure (hazard ratio = 1.83, 95% CI 1.66-2.02, P < 0.001). In subgroup analysis, allograft function (post-transplant time-averaged estimated glomerular filtration rate and cut point: 45 mL/min/1.73 m2) had significant interaction (P = 0.032). The 7-year graft failure rate in recipients with PTA and high eGFR was 7.7% (HR 1.52, 95% CI 1.25-1.84), whereas in those with PTA and low eGFR was 19.9% (HR 2.00, 95% CI 1.74-2.31). CONCLUSIONS The unfavorable impact of PTA was significantly enhanced by low allograft function. PTA is likely to be associated with graft failure due to interaction with allograft function. Therefore, we should consider both Hb level and allograft function while determining the treatment strategy.
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Affiliation(s)
- Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan.
| | - Yasuhiro Okabe
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Unagami
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoichi Kakuta
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan
| | - Junpei Iizuka
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan
| | | | - Tomokazu Shimizu
- Department of Urology, Toda Chuo General Hospital, Saitama, Japan
| | - Kazuya Omoto
- Department of Urology, Toda Chuo General Hospital, Saitama, Japan
| | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan
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12
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Liu H, Ye Y, Chen Y, Zhang Y, Li S, Hu W, Yang R, Zhang Z, Peng H, Lv L, Liu X. Therapeutic targets for the anemia of predialysis chronic kidney disease: a meta-analysis of randomized, controlled trials. J Investig Med 2019; 67:1002-1008. [PMID: 30755495 DOI: 10.1136/jim-2018-000915] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2018] [Indexed: 11/04/2022]
Abstract
Anemia is one of the major complications in predialysis patients with chronic kidney disease (CKD). A clearer cognition of the prognostic impact of hemoglobin (Hb) or hematocrit (Hct) target on the outcomes of predialysis patients with CKD is significant. This article aims to establish the suitable hemoglobin target to provide clinical guidance. MEDLINE, EmBase, the Cochrane Library and other databases were searched with both MeSH terms and keywords to gather researches that assessed all-cause mortality, stroke, treatment of renal replacement, and transfusion. The meta-analysis was accomplished via Revman 5.3 version. Totally, 13 eligible studies involving 7606 patients were included. There was a significantly lower risk of transfusion (risk ratio (RR) 0.59, 95% CI 0.52 to 0.67; p<0.00001) in the higher hemoglobin group than in the lower one. However, no significant difference was found in all-cause mortality (RR 1.10, 95% CI 0.98 to 1.23; p=0.11), stroke (RR 1.32, 95% CI 0.82 to 2.10; p=0.25) and treatment of renal replacement including hemodialysis, peritoneal dialysis and renal transplant (RR 1.08, 95% CI 0.95 to 1.22; p= 0.23) between the higher hemoglobin group and the lower one. The results favor the higher hemoglobin target. To target the higher hemoglobin when treating predialysis patients with CKD may decrease the risk of transfusion without increasing the risk of death, stoke, and treatment of renal replacement.
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Affiliation(s)
- Hongyong Liu
- Division of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital, Meizhou, China
| | - Yuqiu Ye
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanbing Chen
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Yunqiang Zhang
- Division of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital, Meizhou, China
| | - Shaomin Li
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wentao Hu
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rongqian Yang
- Department of Biomedical Engineering, South China University of Technology, Guangdong, China
| | - Zhesi Zhang
- Department of Biomedical Engineering, South China University of Technology, Guangdong, China
| | | | - Linsheng Lv
- Operation Room, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xun Liu
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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13
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Modafferi S, Ries M, Calabrese V, Schmitt CP, Nawroth P, Kopf S, Peters V. Clinical Trials on Diabetic Nephropathy: A Cross-Sectional Analysis. Diabetes Ther 2019; 10:229-243. [PMID: 30617943 PMCID: PMC6349284 DOI: 10.1007/s13300-018-0551-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Treatment options and decisions are often based on the results of clinical trials. We have evaluated the public availability of results from completed, registered phase III clinical trials on diabetic nephropathy and current treatment options. METHODS This was a cross-sectional analysis in which STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. In June 2017, 34 completed phase III clinical trials on diabetic nephropathy in the ClinicalTrials. gov registry were identified and matched to publications in the ClinicalTrials.gov registry and to those in the PubMed and Google Scholar databases. If no publication was identified, the principal investigator was contacted. The ratio of published and non-published studies was calculated. Various parameters, including study design, drugs, and comparators provided, were analyzed. RESULTS Drugs/supplements belonged to 26 different categories of medications, with the main ones being angiotensin-converting enzyme inhibitors, angiotensin-II receptors blockers, and dipeptidyl-peptidase-4-inhibitors. Among the trials completed before 2016 (n = 32), 22 (69%) were published, and ten (31%) remained unpublished. Thus, data on 11 different interventions and more than 1000 patients remained undisclosed. Mean time to publication was 26.5 months, which is longer than the time constrictions imposed by the U.S. Food and Drug Administration Amendments Act. Most trials only showed weak effects on micro- and macroalbuminuria, with an absolute risk reduction of 1.0 and 0.3%, respectively, and the number needed to treat varied between 91 and 333, without any relevant effect on end-stage-renal disease by intensive glucose-lowering treatment. Comparison of the results, however, was difficult since study design, interventions, and the renal outcome parameters vary greatly between the studies. CONCLUSION Despite the financial and human resources involved and the relevance for therapeutic guidelines and clinical decisions, about one-third of phase III clinical trials on diabetic nephropathy remain unpublished. Interventions used in published trials showed a low efficacy on renal outcome. FUNDING Deutsche Forschungsgemeinschaft (DFG): SFB 1118.
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Affiliation(s)
- Sergio Modafferi
- Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Markus Ries
- Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Claus P Schmitt
- Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
| | - Peter Nawroth
- Department of Endocrinology, Diabetology and Clinical Chemistry, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany
- Deutsches Zentrum für Diabetesforschung e.V. (DZD), Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Institute for Diabetes and Cancer, Helmholtz Zentrum, Neuherberg, Germany
| | - Stefan Kopf
- Department of Endocrinology, Diabetology and Clinical Chemistry, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany
- Deutsches Zentrum für Diabetesforschung e.V. (DZD), Neuherberg, Germany
| | - Verena Peters
- Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
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14
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Drüeke TB. Lessons from clinical trials with erythropoiesis-stimulating agents (ESAs). RENAL REPLACEMENT THERAPY 2018. [DOI: 10.1186/s41100-018-0187-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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15
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Finkelstein FO, van Nooten F, Wiklund I, Trundell D, Cella D. Measurement properties of the Short Form-36 (SF-36) and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) in patients with anemia associated with chronic kidney disease. Health Qual Life Outcomes 2018; 16:111. [PMID: 29855366 PMCID: PMC5984470 DOI: 10.1186/s12955-018-0933-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 05/13/2018] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Anemia is a common and debilitating manifestation of chronic kidney disease (CKD). Data from two clinical trials in patients with anemia of CKD were used to assess the measurement properties of the Medical Outcomes Survey Short Form-36 version 2 (hereafter SF-36) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An). The Vitality and Physical functioning domains of the SF-36 and the FACT-An Total, Fatigue and Anemia subscales were identified as domains relevant to CKD-associated anemia. METHODS A total of 204 patients aged 18-80 years were included in the analyses that included internal consistency (Cronbach's alpha), test-retest reliability (intraclass correlation coefficients [ICCs]), convergent and known-groups validity, responsiveness, and estimates of important change. RESULTS Both the SF-36 and the FACT-An had strong psychometric properties with high internal consistency (Cronbach's alpha: 0.69-0.93 and 0.79-0.95), and test-retest reliability (ICCs: 0.64-0.83 and 0.72-0.88). Convergent validity, measured by correlation coefficients between similar concepts in SF-36 and FACT-An, ranged from 0.52 to 0.77. Correlations with hemoglobin (Hb) levels were modest at baseline; by Week 9, the correlations with Hb were somewhat higher, r = 0.23 (p < 0.05) for SF-36 Vitality, r = 0.22 (p < 0.05) for FACT-An Total, r = 0.26 (p < 0.001) for FACT-Fatigue and r = 0.22 (p < 0.01) for Anemia. Correlations with Hb at Week 13/17 were r = 0.28 (p < 0.001) for SF-36 Vitality and r = 0.25 (p < 0.05) for Role Physical; FACT-An Total correlation was r = 0.33 (p < 0.0001), Anemia was r = 0.28 (p < 0.001), and Fatigue was r = 0.30 (p < 0.001). The SF-36 domains and Component Summary scores (p < 0.05-p < 0.0001) demonstrated ability to detect change. For the FACT-An, significant differences (p < 0.05-p < 0.0001) were observed between responder and non-responder change scores: important change score estimates ranged from 2 to 4 for Vitality and 2-3 for Physical functioning. Important change scores were also estimated for the FACT-An Total score (6-9), the Anemia (3-5), and Fatigue subscale (2-4). CONCLUSIONS Both the SF-36 Vitality and Physical function scales and the FACT-An Total, Fatigue and Anemia scales, are reliable and valid measures for assessing health-related quality of life in anemia associated with CKD.
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Affiliation(s)
| | - Floortje van Nooten
- Formerly with Astellas Pharma BV, Sylviusweg 62, 2333 BE Leiden, The Netherlands
| | - Ingela Wiklund
- Evidera, Metro Building, 6th Floor, 1 Butterwick, London, W6 8DL UK
| | - Dylan Trundell
- Formerly with Evidera, Metro Building, 6th Floor, 1 Butterwick, London, W6 8DL UK
| | - David Cella
- Department of Medical Social Sciences, Northwestern University, Evanston, IL USA
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16
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Evans M, Carrero JJ, Bellocco R, Barany P, Qureshi AR, Seeberger A, Jacobson SH, Hylander-Rössner B, Rotnitzky A, Sjölander A. Initiation of erythropoiesis-stimulating agents and outcomes: a nationwide observational cohort study in anaemic chronic kidney disease patients. Nephrol Dial Transplant 2018; 32:1892-1901. [PMID: 27672090 DOI: 10.1093/ndt/gfw328] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 06/14/2016] [Indexed: 11/12/2022] Open
Abstract
Background In 2012, new clinical guidelines were introduced for use of erythropoiesis-stimulating agents (ESA) in chronic kidney disease (CKD) patients, recommending lower haemoglobin (Hb) target levels and thresholds for ESA initiation. These changes resulted in lower blood levels in these patients. However, there is limited evidence on just when ESA should be initiated and the safety of a low Hb initiation policy. Methods In this observational inception cohort study, Swedish, nephology-referred, ESA-naïve CKD patients (n = 6348) were enrolled when their Hb dropped below 12.0 g/L, and they were followed for mortality and cardiovascular events. Four different ESA treatments were evaluated applying dynamic marginal structural models: (i) begin ESA immediately, (ii) begin ESA when Hb <11.0 g/dL, (iii) begin ESA when Hb <10.0 g/dL and (iv) never begin ESA in comparison with 'current practice' [the observed (factual) survival of the entire study cohort]. The adjusted 3-year survival following ESA begun over a range of Hb (from <9.0 to 12.0 g/dL) was evaluated, after adjustment for covariates at baseline and during follow-up. Results Overall, 36% were treated with ESA. Mortality during follow-up was 33.4% of the ESA-treated and 27.9% of the non-treated subjects. The adjusted 3-year survival associated with ESA initiation improved for subjects with initial Hb <9.0 to 11 g/dL and then decreased again for those with Hb above 11.5 g/dL. Initiating ESA at Hb <11.0 g/dL and <10.0 g/dL was associated with improved survival compared with 'current practice' [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.79-0.89 and 0.90; 95% CI 0.86-0.94, respectively] and did not increase the risk of a cardiovascular event (HR 0.93; 95% CI 0.87-1.00). Conclusion In non-dialysis patients with CKD, ESA initiation at Hb < 10.0-11.0 g/dL is associated with improved survival in patients otherwise treated according to guidelines.
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Affiliation(s)
- Marie Evans
- CLINTEC Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Juan-Jesus Carrero
- CLINTEC Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Rino Bellocco
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - Peter Barany
- CLINTEC Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Abdul R Qureshi
- CLINTEC Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Astrid Seeberger
- CLINTEC Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Stefan H Jacobson
- Division of Nephrology, Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
| | - Britta Hylander-Rössner
- CLINTEC Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | | | - Arvid Sjölander
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Metra M, Nodari S, Bordonali T, Bugatti S, Fontanella B, Lombardi C, Saporetti A, Verzura G, Danesi R, Dei Cas L. Anemia and Heart Failure: A Cause of Progression or Only a Consequence? Heart Int 2018. [DOI: 10.1177/1826186807003001-201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Marco Metra
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Savina Nodari
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Tania Bordonali
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Silvia Bugatti
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Benedetta Fontanella
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Carlo Lombardi
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Alberto Saporetti
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Giulia Verzura
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Rossella Danesi
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
| | - Livio Dei Cas
- Section of Cardiovascular Diseases Department of Experimental and Applied Medicine, University of Brescia - Spedali Civili, Brescia - Italy
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18
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Factors Influencing Hemoglobin Variability and Its Association with Mortality in Hemodialysis Patients. ScientificWorldJournal 2018; 2018:8065691. [PMID: 29805324 PMCID: PMC5899870 DOI: 10.1155/2018/8065691] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/25/2017] [Accepted: 01/11/2018] [Indexed: 11/18/2022] Open
Abstract
Purpose We aimed to investigate the factors influencing hemoglobin variability with inflammatory and nutritional parameters and its associations with all-cause mortality among hemodialysis patients. Methods One hundred and sixty-nine patients during the entire 12 months were enrolled into the study. Fasting plasma glucose, creatinine, calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), C-reactive protein (CRP), serum iron, serum iron-binding capacity, and transferrin saturation were analyzed. We defined six groups: low, target range, high, low-amplitude fluctuation with low hemoglobin levels, low-amplitude fluctuation with high hemoglobin levels, and high-amplitude fluctuation. Body mass index (BMI), malnutrition-inflammation score (MIS), and Charlson Comorbidity Index were evaluated. Results Hemoglobin variability was significantly correlated with age, platelet count, and number of hospitalization instances and inversely correlated with erythropoietin dose per body surface area. The coefficient of variation of hemoglobin showed a correlation with MIS and ferritin. The absolute level of hemoglobin showed a negative correlation between PTH, CRP, MIS, number of hospitalization instances and a positive correlation with albumin and BMI. High, low, and target-range groups showed survival advantage compared to the other three groups. In regression analysis, age, CRP levels, MIS, and BMI were the predictors of mortality. Conclusion Inflammation and duration of anemia were the major predictors of hemoglobin variability. High-amplitude fluctuation predicts high mortality; on the contrary low-amplitude fluctuations is related to better survival. MIS was independently associated with mortality. This trial is registered with NCT03454906.
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19
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Wang M, Xin H, Tang W, Li Y, Zhang Z, Fan L, Miao L, Tan B, Wang X, Zhu YZ. AMPK Serves as a Therapeutic Target Against Anemia of Inflammation. Antioxid Redox Signal 2017; 27:251-268. [PMID: 27923278 DOI: 10.1089/ars.2016.6846] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIMS Anemia of inflammation (AI), the second prevalent anemia, is associated with worse prognosis and increased mortality in numerous chronic diseases. We recently reported that the gasotransmitter hydrogen sulfide (H2S) suppressed the inflammatory activation of signal transducer and activator of transcription 3 (STAT3) and hepcidin, the critical mediators of AI. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a novel inflammatory regulator and might be activated by H2S. In this study, we determined whether AMPK played a role in H2S-mediated anti-inflammatory response in AI and evaluated the therapeutic potential of AMPK against AI by pharmacological and clinical approaches. RESULTS We showed that AMPK mediated the inhibition of STAT3, hepcidin, and AI by H2S during inflammation. Moreover, pharmacological and genetic activation of AMPK ameliorated hepcidin production, corrected iron dysregulation, and relieved hypoferremia and anemia in both acute and chronic inflammation models in mice. Mechanistic studies indicated that AMPK suppressed STAT3/hepcidin activation by promoting proteasome-mediated Janus kinase 2 (JAK2) degradation, which was dependent on the intact function of suppressor of cytokine signaling 1 (SOCS1) and increased interactions between SOCS1 and JAK2. Most importantly, the AMPK activator metformin was associated with decreased serum hepcidin content and anemia morbidity in Chinese type 2 diabetes mellitus patients. INNOVATION This is the first study to demonstrate the inhibition of inflammatory hepcidin and AI by AMPK-induced JAK2 degradation. Our work uncovered AMPK as a novel therapeutic target, and metformin as a potential therapy against AI. CONCLUSION The present work demonstrated that AMPK mediated the therapeutic effects of H2S and relieved AI by promoting SOCS1-mediated JAK2 degradation. Antioxid. Redox Signal. 27, 251-268.
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Affiliation(s)
- Minjun Wang
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .,2 Department of Pharmacology, School of Pharmacy, Macau University of Science & Technology , Macau, China
| | - Hong Xin
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China
| | - Wenbo Tang
- 3 Department of Oncology, School of Medicine, Fudan University , Shanghai, China
| | - Yiming Li
- 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China
| | - Zhaoyun Zhang
- 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China
| | - Linling Fan
- 4 Department of Endocrinology, Huashan Hospital, Fudan University , Shanghai, China
| | - Lei Miao
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China
| | - Bo Tan
- 5 Department of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, China
| | - Xiling Wang
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China
| | - Yi Zhun Zhu
- 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .,2 Department of Pharmacology, School of Pharmacy, Macau University of Science & Technology , Macau, China
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Alsayegh F, Waheedi M, Bayoud T, Al Hubail A, Al-Refaei F, Sharma P. Anemia in diabetes: Experience of a single treatment center in Kuwait. Prim Care Diabetes 2017; 11:383-388. [PMID: 28473191 DOI: 10.1016/j.pcd.2017.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/05/2017] [Accepted: 04/10/2017] [Indexed: 11/25/2022]
Abstract
AIMS Diabetes mellitus is the most common metabolic disorder in Kuwait. Anemia is a known outcome of diabetes and its related complications. This study examined the prevalence of anemia in diabetic subjects in Kuwait as well as any association between the presence of anemia with Hemoglobin A1c and diabetes complications. METHODS The study subjects were diabetic patients with complete records and two or more visits at Dasman Diabetes Institute. Patient's data included demographics, complications, medications and laboratory results. Descriptive statistics were applied using SPSS. RESULTS Of 1580 included diabetic patients; the prevalence of anemia was 28.5% (95% CI: 26.3, 30.8). Diabetic females had a higher rate of anemia compared to males (35.8% vs. 21.3% respectively, p<0.001). There was no association between diabetes control (HbA1c) and anemia in both genders (p=0.887). Patients with elevated serum creatinine and microalbuminuria were more likely to be anemic (p<0.001). Diabetic patients with anemia had higher presence of peripheral neuropathy and diabetic foot (p<0.001). CONCLUSION This study shows high prevalence of anemia in diabetic patients, particularly in those with diabetic complications. These results should prompt treatment centers to include anemia investigation and management within their diabetes treatment protocols to reduce morbidity in diabetes.
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Affiliation(s)
| | | | | | | | | | - Prem Sharma
- Health Sciences Center, Kuwait University, Kuwait
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2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease. RENAL REPLACEMENT THERAPY 2017. [DOI: 10.1186/s41100-017-0114-y] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Fliser D, Dellanna F, Koch M, Wiggenhauser A. Early low-dose erythropoiesis-stimulating agent therapy and progression of moderate chronic kidney disease: a randomized, placebo-controlled trial. Nephrol Dial Transplant 2017; 32:279-287. [PMID: 28186540 DOI: 10.1093/ndt/gfw418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 10/25/2016] [Indexed: 01/13/2023] Open
Abstract
Background It is unknown whether early intervention with low-dose erythropoiesis-stimulating agents (ESAs) in non-anaemic patients delays progression of chronic kidney disease (CKD). Methods In a single-blind, 24-month trial, adults with estimated glomerular filtration rate (eGFR) 30–59 mL/min/1.73 m2 and either Type 2 diabetes mellitus or previous kidney transplantation were randomized to low-dose continuous erythropoiesis receptor activator (CERA; monthly dose 30–75 µg; n = 115) or placebo (n = 120). The primary endpoint was the annual change in eGFR (abbreviated Modification of Diet in Renal Disease formula). Results Mean (standard deviation) eGFR was 40.7 (9.8) mL/min/1.73 m2 versus 39.8 (9.2) mL/min/1.73 m2 at baseline for CERA and placebo, respectively, and 39.0 (11.6) g/dL versus 39.7 (10.6) g/dL at the final visit. The median (interquartile range) annual reduction in eGFR was 0.5 (−2.2, 3.8) mL/min/1.73 m2 with CERA versus 0.4 (−2.0, 3.2) mL/min/1.73 m2 with placebo (P = 0.657). No significant difference in the annual change in eGFR was observed between treatment groups in the subpopulations with Type 2 diabetes or kidney transplant. Adverse events with a suspected relation to study drug occurred in 22.0% and 16.2% of patients randomized to CERA or placebo, respectively, and adverse events led to study drug discontinuation in 11.0% and 8.5% of patients. Conclusions Patients with moderate CKD and Type 2 diabetes or previous kidney transplantation showed stable renal function that was unaffected by administration of low-dose ESA. In addition, there was no clinically meaningful effect of 2-year low-dose ESA treatment on albuminuria, an important surrogate marker of kidney injury.
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Affiliation(s)
- Danilo Fliser
- Department of Internal Medicine IV, Saarland University Medical Centre, Kirrbergerstrasse, Homburg/Saar, Germany
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Elliott S, Tomita D, Endre Z. Erythropoiesis stimulating agents and reno-protection: a meta-analysis. BMC Nephrol 2017; 18:14. [PMID: 28077085 PMCID: PMC5225567 DOI: 10.1186/s12882-017-0438-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 01/04/2017] [Indexed: 02/08/2023] Open
Abstract
Background Erythropoiesis stimulating agents (ESAs) were proposed to enhance survival of renal tissues through direct effects via activation of EPO receptors on renal cells resulting in reduced cell apoptosis, or indirect effects via increased oxygen delivery due to increased numbers of Hb containing red blood cells. Thus through several mechanisms there may be benefit of ESA administration on kidney disease progression and kidney function in renal patients. However conflicting ESA reno-protection outcomes have been reported in both pre-clinical animal studies and human clinical trials. To better understand the potential beneficial effects of ESAs on renal-patients, meta-analyses of clinical trials is needed. Methods Literature searches and manual searches of references lists from published studies were performed. Controlled trials that included ESA treatment on renal patients with relevant renal endpoints were selected. Results Thirty two ESA controlled trials in 3 categories of intervention were identified. These included 7 trials with patients who had a high likelihood of AKI, 7 trials with kidney transplant patients and 18 anemia correction trials with chronic kidney disease (predialysis) patients. There was a trend toward improvement in renal outcomes in the ESA treated arm of AKI and transplant trials, but none reached statistical significance. In 12 of the anemia correction trials, meta-analyses showed no difference in renal outcomes with the anemia correction but both arms received some ESA treatment making it difficult to assess effects of ESA treatment alone. However, in 6 trials the low Hb arm received no ESAs and meta-analysis also showed no difference in renal outcomes, consistent with no benefit of ESA/ Hb increase. Conclusions Most ESA trials were small with modest event rates. While trends tended to favor the ESA treatment arm, these meta-analyses showed no reduction of incidence of AKI, no reduction in DGF or improvement in 1-year graft survival after renal transplantation and no significant delay in progression of CKD. These results do not support significant clinical reno-protection by ESAs.
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Affiliation(s)
- Steve Elliott
- Amgen Inc, One Amgen Center, Newbury Park, Thousand Oaks, CA, 91320, USA.
| | - Dianne Tomita
- Amgen Inc, One Amgen Center, Newbury Park, Thousand Oaks, CA, 91320, USA
| | - Zoltan Endre
- Department of Nephrology, Prince of Wales Hospital and Clinical School, University of New South Wales, Sydney, NSW, 2031, Australia
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Poinen K, Oliver MJ, Ravani P, Van der Veer SN, Jager KJ, Van Biesen W, Polkinghorne KR, Rosenfeld A, Lewin AM, Dulai M, Quinn RR. Willingness to participate in a randomized trial comparing catheters to fistulas for vascular access in incident hemodialysis patients: an international survey of nephrologists. Can J Kidney Health Dis 2016; 3:33. [PMID: 27418966 PMCID: PMC4944245 DOI: 10.1186/s40697-016-0125-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 07/02/2016] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Current guidelines favor fistulas over catheters as vascular access. Yet, the observational literature comparing fistulas to catheters has important limitations and biases that may be difficult to overcome in the absence of randomization. However, it is not clear if physicians would be willing to participate in a clinical trial comparing fistulas to catheters. OBJECTIVES We also sought to elicit participants' opinions on willingness to participate in a future trial regarding catheters and fistulas. DESIGN We created a three-part survey consisting of 19 questions. We collected demographic information, respondents' knowledge of the vascular access literature, appropriateness of current guideline recommendations, and their willingness to participate in a future trial. SETTING Participants were recruited from Canada, Europe, Australia, and New Zealand. PARTICIPANTS Participants include physicians and trainees who are involved in the care of end-stage renal disease patients requiring vascular access. MEASUREMENTS Descriptive statistics were used to describe baseline characteristics of respondents according to geographic location. We used logistic regression to model willingness to participate in a future trial. METHODS We surveyed nephrologists from Canada, Europe, Australia, and New Zealand to assess their willingness to participate in a randomized trial comparing fistulas to catheters in incident hemodialysis patients. RESULTS Our results show that in Canada, 86 % of respondents were willing to participate in a trial (32 % in all patients; 54 % only in patients at high risk of primary failure). In Europe and Australia/New Zealand, the willingness to participate in a trial that included all patients was lower (28 % in Europe; 25 % in Australia/New Zealand), as was a trial that included patients at high risk of primary failure (38 % in Europe; 39 % in Australia/New Zealand). Nephrologists who have been in practice for a few years, saw a larger volume of patients, or self-identified as experts in vascular access literature were more likely to participate in a trial. LIMITATIONS Survey distribution was limited to vascular access experts in participating European countries and ultimately led to a discrepancy in numbers of European to non-European respondents overall. Canadian views are likely over-represented in the overall outcomes. CONCLUSIONS Our survey results suggest that nephrologists believe there is equipoise surrounding the optimal vascular access strategy and that a randomized controlled study should be undertaken, but restricted to those individuals with a high risk of primary fistula failure.
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Affiliation(s)
- Krishna Poinen
- />Internal Medicine, University of Calgary, Calgary, Canada
| | | | - Pietro Ravani
- />Faculty of Medicine, University of Calgary, Calgary, Canada
- />Foothills Medical Centre, Cumming School of Medicine, University of Calgary, 1403 29th Street NW, Calgary, AB T2N 2T9 Canada
| | - Sabine N. Van der Veer
- />Institute of Population Health, Health e-Research Centre, University of Manchester, Manchester, UK
| | - Kitty J. Jager
- />Department Medical Informatics, Academic Medical Center, Amsterdam, Netherlands
| | | | | | - Aviva Rosenfeld
- />Australian and New Zealand Society of Nephrology, Melbourne, Australia
| | | | | | - Robert R. Quinn
- />Medicine and Community Health Sciences, University of Calgary, Calgary, Canada
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Dahal S, Cullum BM. Characterization of multiphoton photoacoustic spectroscopy for subsurface brain tissue diagnosis and imaging. JOURNAL OF BIOMEDICAL OPTICS 2016; 21:47001. [PMID: 27086691 DOI: 10.1117/1.jbo.21.4.047001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 03/18/2016] [Indexed: 06/05/2023]
Abstract
The development and demonstration of a multiphoton photoacoustic imaging technique capable of providing high spatial resolution chemical images of subsurface tissue components as deep as 1.4 cm below the tissue surface is described. By combining multiphoton excitation in the diagnostic window (650 to 1100 nm), with ultrasonic detection of nonradiative relaxation events, it is possible to rapidly reconstruct three-dimensional, chemical specific, images of samples underneath overlying structures as well as chemical species of the same material. Demonstration of this technique for subsurface tissue differentiation is shown, with the ability to distinguish between grade III astrocytoma tissue and adjacent healthy tissue in blind studies. By employing photoacoustic signal detection, the high nonradiative relaxation rates of most biological tissue components (>90% >90% ) and the minimal signal attenuation of the resulting ultrasound compensate for excitation efficiency losses associated with two-photon absorption. Furthermore, the two-photon absorption process results in a highly localized excitation volume (ca., 60 μm 60 μm ). Characterization of the probing depth, spatial resolution, and ability to image through overlying structures is also demonstrated in this paper using tissue phantoms with well-characterized optical scattering properties, mimicking those of tissues.
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Okuturlar Y, Akalin N, Kaptanogullari OH, Guner NT, Yilmaz D, Gedikbasi A, Soyluk O, Mert M, Serin SO, Kocoglu H, Hursitoglu M, Kumbasar A. Comparison of serum paraoxonase and arylesterase activities between iron deficiency anemia patients and chronic kidney disease patients with anemia. Ren Fail 2016; 38:781-6. [PMID: 27050633 DOI: 10.3109/0886022x.2016.1162080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Altered paraoxonase (PON) and arylesterase (ARE) activities have been shown in anemic chronic kidney disease (CKD) patients and in iron deficiency anemia (IDA) patients. Whether accompanying anemia alone is responsible for this diminished PON and ARE activities in CKD patients or an additive factor for this is not well studied. Therefore, we tried to clarify this issue here. METHODS A total of 82 subjects that consisted of 19 patients with IDA (group 1), 23 anemic CKD patients (group 2), and 40 age and sex matched healthy subjects (group 3) were enrolled. Carotid intima media thickness (CIMT), serum total thiol (-SH), PON, and ARE activities of the participants were analyzed. RESULTS Group 2 patients had significantly lowest serum levels of Total -SH, PON and ARE. Further comparison showed that total -SH, PON and ARE levels were lower in group 1 than group 3 (p = 0.0001 in both). Regarding comparison of group 1 and 2, only serum ARE levels were significantly lower in group 2 (p = 0.001). PON activity was not different between group 1 and group 2 whereas ARE activity was lower in group 2 than groups 1 and 3. In addition, correlation analysis showed that CIMT was negatively correlated with PON and ARE. CONCLUSIONS This markedly decreased ARE activity in CKD patients, which could not be explained by the anemia alone, may have a role in the pathogenesis of increased atherosclerosis in such patients. Still further studies are needed to certain this.
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Affiliation(s)
- Yildiz Okuturlar
- a Department of Internal Medicine , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Nilgul Akalin
- b Department of Nephrology , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | | | - Nurten Turan Guner
- c Department of Radiology , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Deniz Yilmaz
- a Department of Internal Medicine , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Asuman Gedikbasi
- d Department of Biochemistry , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Ozlem Soyluk
- e Department of Endocrinology and Metabolism , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Meral Mert
- e Department of Endocrinology and Metabolism , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Sibel Ocak Serin
- f Department of Internal Medicine , Umraniye Education and Research Hospital , Istanbul , Turkey
| | - Hakan Kocoglu
- a Department of Internal Medicine , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Mehmet Hursitoglu
- a Department of Internal Medicine , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
| | - Abdulbaki Kumbasar
- a Department of Internal Medicine , Bakirkoy Dr. Sadi Konuk Education and Research Hospital , Istanbul , Turkey
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Gu L, Lou Q, Wu H, Ouyang X, Bian R. Lack of association between anemia and renal disease progression in Chinese patients with type 2 diabetes. J Diabetes Investig 2015; 7:42-7. [PMID: 26816600 PMCID: PMC4718107 DOI: 10.1111/jdi.12368] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 03/31/2015] [Accepted: 04/26/2015] [Indexed: 12/31/2022] Open
Abstract
AIMS/INTRODUCTION Anemia has a close interaction with renal dysfunction in diabetes patients. More proof is still awaited on the relationship between anemia and the progression of renal disease in this population. MATERIALS AND METHODS In the present longitudinal study, 1,645 Chinese type 2 diabetes patients without end-stage renal disease were included in the analysis in Nanjing, China, during January 2006 and December 2012. All patients were managed by staged diabetes management protocol, and clinical parameters were collected at each visit. The end-point of progression of renal disease was evaluated during the follow up. Cox regression analysis was used to estimate the risk of anemia on renal disease progression. RESULTS On recruitment, 350 (21.3%) patients had anemia, which was more common among those with older ages, longer diabetes duration, lower estimated glomerular filtration rate or more albuminura. On median follow up of 49 months (range 28-62 months), 37 patients (2.2%) developed the defined renal end-point. Compared with those without anemia, patients with anemia had a higher risk of renal disease progression. However, multivariate analysis showed that anemia lost its statistical significance once estimated glomerular filtration rate was added into the model. Although the incidence of renal disease progression markedly increased by anemia status in patients of estimated glomerular filtration rate <60 mL/min/1.73 m(2), anemia was still not an independent risk factor for renal disease progression in this subgroup. CONCLUSIONS Anemia was a common finding in Chinese type 2 diabetes patients. Anemia was a risk factor for renal disease progression, but lost its significance once baseline renal function was adjusted.
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Affiliation(s)
- Liubao Gu
- Center for Diabetes Care Education and Research Jiangsu Province Institute of Geriatrics Nanjing China; Department of Endocrinology and Metabolism Jiangsu Province Official Hospital Nanjing China
| | - Qinglin Lou
- Center for Diabetes Care Education and Research Jiangsu Province Institute of Geriatrics Nanjing China; Department of Endocrinology and Metabolism Jiangsu Province Official Hospital Nanjing China
| | - Haidi Wu
- Center for Diabetes Care Education and Research Jiangsu Province Institute of Geriatrics Nanjing China
| | - Xiaojun Ouyang
- Center for Diabetes Care Education and Research Jiangsu Province Institute of Geriatrics Nanjing China; Department of Endocrinology and Metabolism Jiangsu Province Official Hospital Nanjing China
| | - Rongwen Bian
- Center for Diabetes Care Education and Research Jiangsu Province Institute of Geriatrics Nanjing China; Department of Endocrinology and Metabolism Jiangsu Province Official Hospital Nanjing China
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De Nicola L, Locatelli F, Conte G, Minutolo R. Responsiveness to erythropoiesis-stimulating agents in chronic kidney disease: does geography matter? Drugs 2015; 74:159-68. [PMID: 24442793 DOI: 10.1007/s40265-013-0175-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Management of renal anemia in the large and at-risk population of non-dialysis chronic kidney disease (CKD) patients is a critical issue. In particular, definition of the optimal hemoglobin (Hb) target for therapy is controversial but highly warranted by physicians and patients worldwide. Recently, international clinical practice guidelines have recommended delayed initiation of erythropoiesis-stimulating agents (ESA) and lower Hb target levels during maintenance therapy. However, geographical differences in terms of ESA dose needed to achieve a given Hb value can be evidenced, with US patients showing higher prevalence of ESA resistance. On the other hand, non-US patients are often maintained in a higher Hb range by means of low ESA doses. This critical point has never been addressed. Nevertheless, outside of the US, translating the restrictive recommendations of new guidelines, which are essentially based on trials in US patients, can lead to negative effects, such as an increased need for a blood transfusion, and worsening of quality of life. In this article we provide a reappraisal of current recommendations on anemia management in non-dialysis CKD in light of the geographical differences in individual responsiveness to ESA.
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Affiliation(s)
- Luca De Nicola
- Nephrology Division, Second University of Naples, School of Medicine, Piazza Miraglia, 80131, Naples, Italy,
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Palmer SC, Saglimbene V, Mavridis D, Salanti G, Craig JC, Tonelli M, Wiebe N, Strippoli GFM. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev 2014; 2014:CD010590. [PMID: 25486075 PMCID: PMC6885065 DOI: 10.1002/14651858.cd010590.pub2] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies. OBJECTIVES To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high. MAIN RESULTS We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses. AUTHORS' CONCLUSIONS In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.
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Affiliation(s)
- Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, 2 Riccarton Ave, PO Box 4345, Christchurch, 8140, New Zealand.
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Palmer SC, Saglimbene V, Mavridis D, Salanti G, Craig JC, Tonelli M, Wiebe N, Strippoli GFM. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2014. [PMID: 25486075 DOI: 10.1002/14651858.cd010590.pub2.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies. OBJECTIVES To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high. MAIN RESULTS We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses. AUTHORS' CONCLUSIONS In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.
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Affiliation(s)
- Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, 2 Riccarton Ave, PO Box 4345, Christchurch, 8140, New Zealand.
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Alani H, Tamimi A, Tamimi N. Cardiovascular co-morbidity in chronic kidney disease: Current knowledge and future research needs. World J Nephrol 2014; 3:156-168. [PMID: 25374809 PMCID: PMC4220348 DOI: 10.5527/wjn.v3.i4.156] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/30/2014] [Accepted: 10/16/2014] [Indexed: 02/05/2023] Open
Abstract
Chronic kidney disease (CKD) is recognised as a health concern globally and leads to high rates of morbidity, mortality and healthcare expenditure. CKD is itself an independent risk factor for unfavorable health outcomes that include cardiovascular disease (CVD). Coronary artery disease is the primary type of CVD in CKD patients and a significant cause of death among renal transplant patients. Traditional and non-traditional risk factors for CVD exist in patients with CKD. Traditional factors include smoking, hypertension, dyslipidemia and diabetes which are highly prevalent in CKD patients. Non-traditional risk factors of CKD are mainly uraemia-specific and increase in prevalence as kidney function declines. Some examples of uraemia-specific risk factors that have been well documented include low levels of haemoglobin, albuminuria, and abnormal bone and mineral metabolism. Therapeutic interventions targeted at more traditional risk factors which contribute to CVD, have not had the desired effect on lowering CVD events and mortality in those suffering with CKD. Future research is warranted to delineate clear evidence to the benefit of modifying non-traditional risk factors.
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Covic A, Nistor I, Donciu MD, Dumea R, Bolignano D, Goldsmith D. Erythropoiesis-stimulating agents (ESA) for preventing the progression of chronic kidney disease: a meta-analysis of 19 studies. Am J Nephrol 2014; 40:263-79. [PMID: 25323019 DOI: 10.1159/000366025] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND The effect of anemia correction on kidney function in chronic kidney disease (CKD) patients remains unclear. As 19-40% of patients with CKD receive an erythropoiesis-stimulating agent (ESA), this is a potentially important consideration. SUMMARY We conducted a systematic review and meta-analysis of randomized trials to January 1, 2014 in adult patients with CKD stages 1 to 4. SELECTION CRITERIA FOR STUDIES randomized controlled trials of at least 2 months duration. Patients were allocated to ESA versus placebo, no treatment, or different ESA doses with the purpose of achieving a higher versus a lower hemoglobin target. The analyzed outcomes were the need for renal replacement therapy, doubling of serum creatinine, change in GFR (ml/min), mortality and withdrawal of treatment due to adverse events. A total of 19 trials (n = 8,129 participants with CKD stage 1-4) were reviewed. There was no difference in the risk of end-stage kidney disease (RR, 0.97 [CI 0.83-1.20], 17 trials, 8,104 participants), change in GFR (Mean Difference [MD] -0.45 [-2.21, 1.31], 9 trials, 1,848 participants) or withdrawal of treatment due to adverse events (RR, 1.18 [CI 0.77-1.81], 10 trials, n = 1,958 participants) for patients at higher hemoglobin (Hb) targets. Furthermore, no statistically significant differences in mortality (Risk Ratio [RR] 1.10 [CI 0.90-1.35], 16 trials, n = 8,082 participants) were observed. Key Messages: There is no evidence that ESA treatment affects renal function in patients with CKD. Use of these agents should not therefore be influenced by considerations about influencing CKD progression.
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Affiliation(s)
- Adrian Covic
- Nephrology Department, Faculty of Medicine, University of Medicine and Pharmacy 'Gr. T. Popa', Iasi, Romania
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de Goeij MCM, Meuleman Y, van Dijk S, Grootendorst DC, Dekker FW, Halbesma N. Haemoglobin levels and health-related quality of life in young and elderly patients on specialized predialysis care. Nephrol Dial Transplant 2014; 29:1391-8. [DOI: 10.1093/ndt/gft533] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Minutolo R, Locatelli F, Gallieni M, Bonofiglio R, Fuiano G, Oldrizzi L, Conte G, De Nicola L, Mangione F, Esposito P, Dal Canton A. Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics. Nephrol Dial Transplant 2013; 28:3035-3045. [PMID: 24145459 DOI: 10.1093/ndt/gft338] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement. METHODS We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from ≥6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID. RESULTS Age was 69 ± 13 years and GFR 27.5 ± 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively). CONCLUSIONS This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment.
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Affiliation(s)
- Roberto Minutolo
- Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell'Invecchiamento, Seconda Università di Napoli, Piazzale V. Tecchio 29, 80125 Napoli, Italy
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Ajmal A, Gessert CE, Johnson BP, Renier CM, Palcher JA. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on hemoglobin levels. BMC Res Notes 2013; 6:443. [PMID: 24188157 PMCID: PMC4228356 DOI: 10.1186/1756-0500-6-443] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 10/25/2013] [Indexed: 11/11/2022] Open
Abstract
Background Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in the management of congestive heart failure (CHF), diabetes mellitus (DM) and hypertension (HTN). Use of these agents is reported to cause anemia. Methods We examined the association between standard care use of ACEI or ARB and subsequent change in hemoglobin (Hgb) in a population of 701 adult primary care patients with DM, CHF and/or HTN. Data analysis was conducted to adjust for baseline differences between the treatment groups. Results After adjusting for differences in covariates at baseline between the subjects who were prescribed ACEI (N = 519) and ARB (N = 182), as well as the associated odds of being prescribed ARB, the ACEIs were associated with lower mean Hgb [0.18 (0.02, 0.34) g/dL, p = 0.02] at follow up relative to ARBs. However, patients with CHF experienced an increase in Hgb while on treatment (0.42 g/dL), especially those treated with ACEIs (0.56 g/dL). Chronic kidney disease at baseline was not associated with a significant decrease in Hgb in either treatment group. Conclusions Since ACEIs and ARBs are most frequently used in patients who are vulnerable to complications from anemia, such as patients with CHF, HTN and DM, these findings may be useful to clinicians in selecting medications and monitoring patients for the adverse effects of treatment.
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Akaishi M, Hiroe M, Hada Y, Suzuki M, Tsubakihara Y, Akizawa T. Effect of anemia correction to the modestly high hemoglobin level in patients with chronic kidney disease on left ventricular hypertrophy. J Cardiol 2013; 62:249-56. [DOI: 10.1016/j.jjcc.2013.04.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 04/15/2013] [Accepted: 04/22/2013] [Indexed: 01/12/2023]
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Akizawa T, Saito A, Gejyo F, Suzuki M, Nishizawa Y, Tomino Y, Tsubakihara Y, Akiba T, Hirakata H, Watanabe Y, Kawanishi H, Bessho M, Udagawa Y, Aoki K, Uemura Y, Ohashi Y. Impacts of Recombinant Human Erythropoietin Treatment During Predialysis Periods on the Progression of Chronic Kidney Disease in a Large-Scale Cohort Study (Co-JET study). Ther Apher Dial 2013; 18:140-8. [DOI: 10.1111/1744-9987.12066] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Tadao Akizawa
- Division of Nephrology; Department of Medicine; Showa University School of Medicine; Tokyo Japan
| | | | - Fumitake Gejyo
- Niigata University Graduate School of Medical and Dental Sciences; Niigata Japan
| | | | | | - Yasuhiko Tomino
- Division of Nephrology; Department of Internal Medicine; Juntendo University Faculty of Medicine; Tokyo Japan
| | - Yoshiharu Tsubakihara
- Department of Comprehensive Kidney Disease Research; Osaka University Graduate School of Medicine; Osaka Japan
| | - Takashi Akiba
- Department of Blood Purification; Kidney Center; Tokyo Women's Medical University; Tokyo Japan
| | - Hideki Hirakata
- Department of Nephrology; Fukuoka Red Cross Hospital; Fukuoka Japan
| | - Yuzo Watanabe
- Department of Internal Medicine; Kasugai Municipal Hospital; Nagoya Japan
| | - Hideki Kawanishi
- Department of Artificial Organs; Tsuchiya General Hospital; Hiroshima Japan
| | - Masami Bessho
- Department of Hematology; Saitama Medical School; Saitama Japan
| | - Yukio Udagawa
- Pharmacovigilance Department; Chugai Pharmaceutical Co., Ltd.; Tokyo Japan
| | - Kotonari Aoki
- Pharmacovigilance Department; Chugai Pharmaceutical Co., Ltd.; Tokyo Japan
| | - Yukari Uemura
- Department of Biostatistics, School of Public Health; The University of Tokyo; Tokyo Japan
| | - Yasuo Ohashi
- Department of Biostatistics, School of Public Health; The University of Tokyo; Tokyo Japan
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Abstract
Anaemia is a common finding in people with diabetes and chronic kidney disease and failure of the kidney to produce erythro-poietin in response to a falling haemoglobin concentration is a key component, correlating with the degree of albuminuria, renal dysfunction and iron deficiency. Anaemia in diabetes is associated with a number of adverse outcomes, including increased risk of all cause and cardiovascular mortality. Whether or not anaemia is a marker or mediator of adverse outcome still remains to be completely resolved. Treatment of anaemia in diabetes has quality of life benefits and reduces transfusion requirements. Correction of anaemia to normal haemoglobin concentrations is associated with significant adverse cardiovascular outcomes and is not recommended, escalating doses of erythropoiesis-stimulating agents should be avoided. The treatment of anaemia in people with diabetes and chronic kidney disease should begin with optimisation of iron stores. An aspirational haemoglobin concentration range of 10-12 g/dl with anaemia management, balances proven benefits of anaemia treatment with potential cardiovascular risk.
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Affiliation(s)
- P E Stevens
- Kent and Canterbury Hospital, Canterbury, Kent, UK.
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Suzuki M, Hada Y, Akaishi M, Hiroe M, Aonuma K, Tsubakihara Y, Akizawa T. Effects of anemia correction by erythropoiesis-stimulating agents on cardiovascular function in non-dialysis patients with chronic kidney disease. Int Heart J 2012; 53:238-43. [PMID: 22878802 DOI: 10.1536/ihj.53.238] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Anemia is a significant risk factor for patients with chronic kidney disease (CKD). Here, we investigated the effects of anemia correction on cardiac functions in CKD patients. Pre-dialysis CKD patients (n = 171) without known risk factors for cardiovascular disease (CVD) other than CKD with hemoglobin (Hb) concentrations < 10.0 g/dL were enrolled for evaluation of cardiac functions and biomarkers before and after the 16-week treatment of erythropoiesis-stimulating agents. The treatment significantly increased Hb concentrations in all patients who completed the study (n = 143, 8.91 ± 0.87 versus 11.27 ± 1.31 g/dL; n < 0.001) and among patients whose echocardiograms were available for evaluation (n = 77, 8.92 ± 0.94 versus 11.24 ± 1.13 g/dL; P < 0.001). The left ventricular mass index (LVMI) was decreased (121.3 ± 25.8 versus 114.7 ± 25.1 g/m(2), n = 77, P = 0.012) and significant correlation between the change in the LVMI and Hb concentration was noted (P = 0.011). The levels of B-type natriuretic peptide and human atrial natriuretic peptide, and the cardio-thoracic ratio were significantly increased among subjects with Hb concentrations < 11.0 g/dL at completion of the study. The changes in these parameters were significantly correlated with the Hb concentrations (P = 0.033, P = 0.011, and P < 0.001, respectively). No significant differences were observed in the electrocardiographic parameters. Correcting Hb levels higher than those conventionally recommended reduced left ventricular hypertrophy and myocardial stress, lowering risks for CVD in pre-dialysis CKD patients.
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Affiliation(s)
- Makoto Suzuki
- Department of Clinical Laboratory, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan
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Jing Z, Wei-jie Y, Nan Z, Yi Z, Ling W. Hemoglobin targets for chronic kidney disease patients with anemia: a systematic review and meta-analysis. PLoS One 2012; 7:e43655. [PMID: 22952731 PMCID: PMC3431367 DOI: 10.1371/journal.pone.0043655] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2012] [Accepted: 07/23/2012] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Numerous studies have identified a relationship between hemoglobin (Hb) levels and mortality in patients with chronic kidney disease (CKD), which have raised concerns about the optimal Hb targets in correction of anemia. Our study is designed to investigate the potential effects of targeted Hb levels, aiming to give some evidence for therapy of renal anemia. METHODOLOGY/PRINCIPAL FINDINGS A comprehensive search of Medline, Embase and the Cochrane Database of Systematic Reviews was performed in December 2011 and updated in February 2012 for any new trials. Randomized trials designed to evaluate effects of high (generally the Hb about 13.0 g/dL) and low Hb (generally the Hb about 10.0 g/dL) targets on clinical outcomes in CKD patients with anemia were collected. All statistical analysis was calculated using the RevMan software available free from the Cochrane Collaboration. 24 trials involving 10361 patients were identified. Our findings demonstrated a statistically significant increased risk of mortality in the high Hb levels (RR 1.18; 95% CI 1.02 to 1.37) while the high and low Hb groups were both treated with ESAs. Overall, compared with low Hb levels, high Hb levels are associated with increased risk of hypertension (RR 1.40; 95% CI 1.11 to 1.75), stroke (RR 1.73; 95% CI 1.31 to 2.29), and hospitalizations (RR 1.07; 95% CI 1.01 to 1.14). However, there are no significant differences in the risk of non-fatal myocardial infarction (RR 1. 13; 95% CI 0.79 to 1.61) and renal replacement therapy (RR 1. 00; 95% CI 0.85 to 1.18). CONCLUSIONS/SIGNIFICANCES Targeting low Hb levels are beneficial to CKD patients especially in the predialysis population. The optimal Hb targets to aim for in CKD patients and at what Hb level the risks of adverse events begin to increase remain elusive. Future studies are still needed to elucidate these questions.
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Affiliation(s)
- Zhou Jing
- Department of Nephrology The First People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Yuan Wei-jie
- Department of Nephrology The First People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
- * E-mail:
| | - Zhu Nan
- Department of Nephrology The First People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Zhou Yi
- Department of Nephrology The First People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Wang Ling
- Department of Nephrology The First People's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
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Koulouridis I, Alfayez M, Trikalinos TA, Balk EM, Jaber BL. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. Am J Kidney Dis 2012; 61:44-56. [PMID: 22921639 DOI: 10.1053/j.ajkd.2012.07.014] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 07/25/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk. STUDY DESIGN Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level. SETTING & POPULATION Patients with anemia of CKD irrespective of dialysis status. SELECTION CRITERIA FOR STUDIES We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis. PREDICTORS ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels. OUTCOMES All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement. RESULTS 31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events. LIMITATIONS Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders. CONCLUSIONS In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.
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Affiliation(s)
- Ioannis Koulouridis
- Department of Medicine, Division of Nephrology, Kidney and Dialysis Research Laboratory, St. Elizabeth's Medical Center, Boston, MA 02135, USA
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Tawadrous H, Kamran H, Salciccioli L, Schoeneman MJ, Lazar J. Evaluation of arterial structure and function in pediatric patients with end-stage renal disease on dialysis and after renal transplantation. Pediatr Transplant 2012; 16:480-5. [PMID: 22624620 DOI: 10.1111/j.1399-3046.2012.01721.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
CVD is a major cause of morbidity and mortality in pediatric patients with CKD. It is unclear whether vascular abnormalities in these patients are reversible, and if transplantation portends salutary effects on arterial function. We compared FMD, PWV, AI75, and CIMT in 15 dialysis (D), 14 transplant patients (T), and 15 controls (C), and their associations with cardiovascular risk factors. There was stepwise lower FMD (p < 0.001), higher AI75 (p < 0.001), higher PWV (p = 0.01), and higher CIMT SDS for age (p = 0.03) and height (p = 0.006) in the D group than T and C groups. FMD, PWV, and CIMT were unrelated to dialysis duration or time from transplantation. On multivariate analysis, group status was independently associated with FMD (β = 3.15, p = 0.002), AI75 (β = -5.95, p = 0.01), PWV (β = -0.57, p = 0.07) and CIMT (β = -0.02, p = 0.04) and CIMT SDS for height (β = -0.541, p = 0.009). FMD is lower and AI75, PWV and CIMT are higher in pediatric patients maintained on D than T/C. T patients have similar AI75, PWV and CIMT to C although FMD remains reduced. These findings suggest that transplantation stabilizes or improves CKD associated arteriopathy.
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Affiliation(s)
- Hanan Tawadrous
- Department of Pediatrics, Division of Pediatric Nephrology, State University of New York Downstate Medical Center, Brooklyn, NY, USA
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Minutolo R, Conte G, Cianciaruso B, Bellizzi V, Camocardi A, De Paola L, De Nicola L. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant 2012; 27:2880-6. [PMID: 22319218 DOI: 10.1093/ndt/gfs007] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Lower responsiveness to erythropoiesis-stimulating agents (ESA-R) predicts cardiovascular (CV) events. Whether ESA-R also affects the risk of end-stage renal disease (ESRD) is unknown. METHODS We evaluated ESA-R in 194 consecutive chronic kidney disease (CKD) patients, regularly seen in outpatient nephrology clinics, who started erythropoiesis-stimulating agent (ESA) therapy between 2002-06. Exclusion criteria were causes of anaemia other than CKD or recent transfusion. ESA-R was calculated as (Hb1-Hb0)/time/ESA dose (g/dL/month/10 μg/week of ESA). Patients were classified, from lower to higher tertile of ESA-R, as poor, intermediate and good responders. Time to ESRD was the primary outcome. RESULTS Age was 64±16 years, 48% were male, 34% had diabetes and 32% had CV disease, glomerular filtration rate (GFR) 24±13 mL/min/1.73 m2 and proteinuria 0.6 g/dL (interquartile range 0.2-1.9). First ESA dose was 23.7±10.8 μg/week; haemoglobin (Hb) increased from 9.9±0.8 g/dL to 11.0±1.2 g/dL at first control, obtained after 1.4±0.4 months. These changes corresponded to an ESA-R of 0.37±0.38 g/dL/month/10 μg/week of ESA and tertiles limits were 0.17 and 0.47. Poor responders were younger and had lower GFR and higher proteinuria than intermediate and good responders. During the first 6 months of ESA therapy, poor responders showed lower Hb levels and sustained longer periods of Hb level<11 g/dL. During follow-up (median 3.0 years), 99 patients reached ESRD. At multivariable Cox's analysis, poor responsiveness was associated with higher risk of ESRD (hazard ratio 2.49, 95% confidence interval 1.28-4.84). CONCLUSION ESA-R predicts renal prognosis in CKD patients followed in nephrology practice, where ESRD is the predominant outcome and ESA is commonly used at low dose.
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Affiliation(s)
- Roberto Minutolo
- Division of Nephrology, Second University of Naples, Naples, Italy.
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Sasatomi Y, Ito K, Abe Y, Miyake K, Ogahara S, Nakashima H, Saito T. Association of Hypoalbuminemia with Severe Anemia in Patients with Diabetic Nephrosclerosis. Ren Fail 2012; 34:189-93. [DOI: 10.3109/0886022x.2011.646885] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Al-Ageel NA, Al-Aqeel SA, Abanmy NO, Alwakeel JS, Sabry A, Alsaran KA. Appropriateness of anemia management in hemodialysis patients. Saudi Pharm J 2012; 20:85-91. [PMID: 23960781 DOI: 10.1016/j.jsps.2011.08.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 08/17/2011] [Indexed: 11/24/2022] Open
Abstract
UNLABELLED The anemia of end stage renal disease (ESRD) is common and often severe complication that can be managed successfully by erythropoiesis-stimulating agents (ESA) administration. AIMS To investigate current practice of anemia management in hemodialysis patients and to assess the appropriateness of anemia management by comparing observed practice to the Kidney Disease Outcomes Quality Initiative (KDOQI) guideline recommendations. SETTINGS AND DESIGN The study was conducted at two hemodialysis centers in Riyadh, Saudi Arabia. Data on anemia parameters, comorbidities, ESA dosing and iron supplementation were collected. The data were collected for 7 months retrospectively from April to the end of May 2008 and prospectively from June to October 2008. Patients who were over 18 years of age with ESRD undergoing hemodialysis were included. Patients were excluded if they have cancer or receiving chemotherapy or radiotherapy. RESULTS Data were collected from 87 patients. Mean Hgb value for those patients was 11.16 ± 0.97 g/dL. Thirty-nine patients (45%) had mean Hgb values between 11.0 and 12.0 g/dL the target range recommended by KDOQI guideline. The mean weekly prescribed dose of erythropoietin was 8099 ± 5946 IU/Week (135 ± 99 IU/kg/Week). Information on ferritin concentrations was available for 48 (55%) patients. The mean serum ferritin concentration for those patients was 693 ± 420.5 ng/mL. Fifty-two patients had transferrin saturation (TSAT) values recorded. The mean TSAT value was 38.5 ± 19.7%. CONCLUSIONS There is an opportunity to improve anemia management in hemodialysis patients particularly thorough evaluation of causes of inadequate response rate and better monitoring and management of iron status.
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Affiliation(s)
- Nahla A Al-Ageel
- Department of Clinical Pharmacy, King Saud University, Saudi Arabia
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Rottembourg JB, Dansaert A. Faisabilité de la stratégie d’administration de la darbepoetin alfa tous les 15 jours : expérience 2005–2007 d’un centre de dialyse. Nephrol Ther 2011; 7:549-57. [DOI: 10.1016/j.nephro.2011.03.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 03/15/2011] [Accepted: 03/27/2011] [Indexed: 10/15/2022]
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Fliser D, Dellanna F, Koch M, Seufert J, Witzke O, Hauser I. The PRIMAVERA study protocol design: Evaluating the effect of continuous erythropoiesis receptor activator (C.E.R.A.) on renal function in non-anemic patients with chronic kidney disease. Contemp Clin Trials 2011; 32:786-92. [DOI: 10.1016/j.cct.2011.06.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 06/22/2011] [Accepted: 06/28/2011] [Indexed: 10/18/2022]
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Pritchett Y, Jemiai Y, Chang Y, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata-Andía JB, Thompson T, Appelbaum E, Audhya P, Andress D, Zhang W, Solomon S, Manning WJ, Thadhani R. The use of group sequential, information-based sample size re-estimation in the design of the PRIMO study of chronic kidney disease. Clin Trials 2011; 8:165-74. [PMID: 21478328 DOI: 10.1177/1740774511399128] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies. PURPOSE PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease. METHODS Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis. LIMITATIONS If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making. CONCLUSIONS The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.
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Villar E, Lièvre M, Kessler M, Lemaître V, Alamartine E, Rodier M, François M, Zaoui P, Moranne O, Choukroun G, Guerraoui A, Jolivot A, Janin G, Branger B, Heng AE, Boudray C, Bissery A, Rabilloud M, Pouteil-Noble C. Anemia normalization in patients with type 2 diabetes and chronic kidney disease: results of the NEPHRODIAB2 randomized trial. J Diabetes Complications 2011; 25:237-43. [PMID: 21601481 DOI: 10.1016/j.jdiacomp.2011.03.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 02/22/2011] [Accepted: 03/08/2011] [Indexed: 11/30/2022]
Abstract
STATEMENTS OF THE PROBLEM Correction of anemia in type 2 diabetes (T2DM) patients with chronic kidney disease stages 3-4 may slow the decline of kidney function but may increase cardiovascular risk through higher hematocrit. The NEPHRODIAB2 study was designed to assess efficacy and safety of complete hemoglobin (Hb) normalization in these patients. METHODS We randomly assigned 89 T2DM patients with an estimated glomerular filtration rate (eGFR; abbreviated 175 Modification of Diet in Renal Disease formula) of 25 to 60 ml/min per 1.73 m(2) and moderate anemia (Hb, 100-129 g/l) to a target Hb value in subnormal range (110-129g/l, group 1, n=43) or normal range (130-149 g/l, group 2, n=46). The primary end point was eGFR decline after 2 years of follow-up. Secondary end points included iron and erythropoietin dosage, quality of life (Medical Outcomes Study 36-item Short-Form Health Survey scores) and adverse events. RESULTS Six months after randomization, the mean Hb levels were <120 g/l in group 1 and >130 g/l in group 2 (P<.05 at 6, 12, 18 and 24 months). Blood pressure, 24-h proteinuria and HbA1c did not differ during follow-up (P>.05). Two-year declines in eGFR were -8.7±12.2 in group 1 and -5.1±7.8 ml/min per 1.73 m(2) in group 2 (P=.29). Mean weekly use of erythropoietin was 7.8±11.6 μg in group 1 and 30.1±33.6 μg in group 2 (P<.0001). There was no significant difference regarding Medical Outcomes Study 36-item Short-Form Health Survey score change or adverse event occurrence. CONCLUSIONS In this trial, normalization of Hb level in T2DM patients with chronic kidney disease was safe but did not significantly slow renal function decline and increased treatment cost due to erythropoietin use.
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Affiliation(s)
- Emmanuel Villar
- Hospices Civils de Lyon, Department of Nephrology, Lyon Sud Hospital, Pierre Benite, France.
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Akizawa T, Gejyo F, Nishi S, Iino Y, Watanabe Y, Suzuki M, Saito A, Akiba T, Hirakata H, Fukuhara S, Morita S, Hiroe M, Hada Y, Suzuki M, Akaishi M, Iwasaki M, Tsubakihara Y. Positive outcomes of high hemoglobin target in patients with chronic kidney disease not on dialysis: a randomized controlled study. Ther Apher Dial 2011; 15:431-40. [PMID: 21974695 DOI: 10.1111/j.1744-9987.2011.00931.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Correcting anemia in patients with chronic kidney disease (CKD) to higher hemoglobin (Hb) levels may be associated with increased risk. No optimal target for Hb has been established. This controlled study examined 321 patients with CKD who were not on dialysis, had a Hb level of <10g/dL, and a serum creatinine of 2.0 to 6.0mg/dL. They were randomized into two target Hb groups: 161 to high Hb (11.0-13.0g/dL) to receive darbepoetin alfa and low Hb to 160 (9.0-11.0g/dL) to receive recombinant erythropoietin. The study lasted 48weeks. Of 154 and 153 patients with adverse events, cardiovascular adverse events developed in 42 and 51 patients in the high and low Hb groups, respectively, with no significant difference in the incidence. All quality of life scores improved in the high Hb group and vitality improved significantly more with high Hb (P=0.025). The left ventricular mass index (LVMI) remained stable in the low Hb group, but there was a significant decrease in LVMI in the high group (P<0.001). There were no safety concerns with targeting a higher Hb level during the 48weeks of this study. Patients with a higher Hb target had comparatively better outcomes with respect to quality of life and LVMI.
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Affiliation(s)
- Tadao Akizawa
- Showa University School of Medicine Nippon Medical School Hospital Tokyo, Japan.
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