FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1571358690> ?p ?o ?g. }

• W1571358690 endingPage "914" @default.
• W1571358690 startingPage "905" @default.
• W1571358690 abstract "Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m2, intravenous -4.0 ml/min per 1.73 m2, between-group difference -0.35 ml/min per 1.73 m2; 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56–4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24–3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases. Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m2, intravenous -4.0 ml/min per 1.73 m2, between-group difference -0.35 ml/min per 1.73 m2; 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56–4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24–3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases. It is estimated that there are ∼8 million individuals in the United States with moderate-to-severe chronic kidney disease (CKD).1.Coresh J. Wei G.L. McQuillan G. et al.Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988-1994).Arch Intern Med. 2001; 161: 1207-1216Crossref PubMed Scopus (495) Google Scholar Anemia often occurs during moderate (stage 3) CKD, primarily from reduced erythropoietin production but also because of iron deficiency.2.Fishbane S. Pollack S. Feldman H.I. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988-2004.Clin J Am Soc Nephrol. 2009; 4: 57-61Crossref PubMed Scopus (125) Google Scholar Enhanced erythropoiesis after therapy with recombinant human erythropoietin may lead to functional iron deficiency that often necessitates therapy with intravenous (IV) iron.3.Nissenson A.R. Strobos J. Iron deficiency in patients with renal failure.Kidney Int Suppl. 1999; 69: S18-S21Abstract Full Text Full Text PDF PubMed Google Scholar Although partial correction of anemia reduces the need for blood transfusions, toxicity due to the participation of elemental iron in causing cell damage and in generating oxidative stress has raised concern of potential health risks that remain incompletely understood.4.Besarab A. Iron and cardiac disease in the end-stage renal disease setting.Am J Kidney Dis. 1999; 34: S18-S24Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar,5.Besarab A. Frinak S. Yee J. An indistinct balance: the safety and efficacy of parenteral iron therapy.J Am Soc Nephrol. 1999; 10: 2029-2043PubMed Google Scholar There is a paucity of information on the safety of this therapy as only one-half of the randomized clinical trials of oral and IV iron in adults and children reported adverse events, and even fewer described those that were serious.6.Albaramki J. Hodson E.M. Craig J.C. et al.Parenteral versus oral iron therapy for adults and children with chronic kidney disease.Cochrane Database Syst Rev. 2012; 1: CD007857PubMed Google Scholar Oxidative stress plays an important role in the pathogenesis and progression of CKD.7.Haugen E. Nath K.A. The involvement of oxidative stress in the progression of renal injury.Blood Purif. 1999; 17: 58-65Crossref PubMed Scopus (121) Google Scholar,8.Klahr S. Oxygen radicals and renal diseases.Miner Electrolyte Metab. 1997; 23: 140-143PubMed Google Scholar Iron increases biological markers of oxidative stress9.Agarwal R. Warnock D. Issues related to iron replacement in chronic kidney disease.Semin Nephrol. 2002; 22: 479-487Abstract Full Text PDF PubMed Scopus (30) Google Scholar in cell cultures,10.Zager R.A. Johnson A.C. Hanson S.Y. et al.Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury.Am J Kidney Dis. 2002; 40: 90-103Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar animal models,11.Shah S.V. Role of iron in progressive renal disease.Am J Kidney Dis. 2001; 37: S30-S33Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar and among end-stage renal disease patients treated with hemodialysis.12.Handelman G.J. Walter M.F. Adhikarla R. et al.Elevated plasma F2-isoprostanes in patients on long-term hemodialysis.Kidney Int. 2001; 59: 1960-1966Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 13.Spittle M.A. Hoenich N.A. Handelman G.J. et al.Oxidative stress and inflammation in hemodialysis patients.Am J Kidney Dis. 2001; 38: 1408-1413Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 14.Salahudeen A.K. Oliver B. Bower J.D. et al.Increase in plasma esterified F2-isoprostanes following intravenous iron infusion in patients on hemodialysis.Kidney Int. 2001; 60: 1525-1531Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Among patients with CKD not on dialysis, IV iron can generate oxidative stress and downstream effects such as endothelial damage and kidney injury.15.Agarwal R. Vasavada N. Sachs N.G. et al.Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease.Kidney Int. 2004; 65: 2279-2289Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar,16.Agarwal R. Leehey D.J. Olsen S.M. et al.Proteinuria induced by parenteral iron in chronic kidney disease—a comparative randomized controlled trial.Clin J Am Soc Nephrol. 2011; 6: 114-121Crossref PubMed Scopus (25) Google Scholar Thus, iron-induced injury may lead to an accelerated course of renal7.Haugen E. Nath K.A. The involvement of oxidative stress in the progression of renal injury.Blood Purif. 1999; 17: 58-65Crossref PubMed Scopus (121) Google Scholar and cardiovascular disease.17.Drueke T. Witko-Sarsat V. Massy Z. et al.Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease.Circulation. 2002; 106: 2212-2217Crossref PubMed Scopus (345) Google Scholar,18.Becker B.N. Himmelfarb J. Henrich W.L. et al.Reassessing the cardiac risk profile in chronic hemodialysis patients: a hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors.J Am Soc Nephrol. 1997; 8: 475-486PubMed Google Scholar Research recommendations emphasize the need to evaluate the long-term risks of IV iron therapy among CKD patients.19.Kidney Disease Improving Global Outcomes (KDIGO) Anemia Work Group KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (668) Google Scholar We hypothesized that among patients with moderate-to-severe CKD and iron deficiency anemia (IDA), compared with oral iron, infusion of IV iron will result in greater decline in kidney function. We report here the primary results of the REVOKE (randomized trial to evaluate intravenous and oral iron in chronic kidney disease). Between 15 August 2008 and 20 October 2014, we randomized 136 subjects with iron deficiency anemia (IDA) and CKD not on dialysis to either oral iron sulfate or IV iron sucrose. The trial flow is shown in the Supplementary Appendix (Supplementary Figure S1 online). Download .doc (.52 MB) Help with doc files Supplementary Information The clinical characteristics of study participants at baseline are shown in Table 1. Of note, compared with the oral iron group, the IV iron group was younger (P=0.02) and had less baseline cardiovascular disease (P=0.04) and past history of hospitalization due to infection (P=0.05). Overall, the mean hemoglobin concentration at baseline was 10.6 g/dl, transferrin saturation 17.3%, and serum ferritin 153 ng/ml. At baseline, erythopoiesis stimulating agents were used by only 8.1% of the participants. Mean measured glomerular filtration rate (mGFR) was 34.5 ml/min per 1.73 m2 and proteinuria had a geometric mean of 0.5 g per g creatinine. The median follow up (interquartile range) of all participants was 24.0 months (11.0–24.3) and did not differ by treatment group assignment.Table 1Baseline characteristics of the study sample, overall and by treatment group assignmentClinical characteristicOral iron (n=69)Intravenous iron (n=67)All subjects (n=136)Age (years)67.8±11.563.2±10.765.5±11.3Male sex, n (%)54 (78.3%)50 (74.6%)104 (76.5%)Blacks, n (%)18 (26.1%)27 (40.3%)45 (33.1%)Hispanic, n (%)0 (0%)2 (3%)2 (1.5%)Etiology of chronic kidney disease Diabetes mellitus, n (%)30 (43.5%)29 (43.3%)59 (43.4%) Hypertension, n (%)20 (29%)19 (28.4%)39 (28.7%) Ischemic kidney disease, n (%)5 (7.2%)3 (4.5%)8 (5.9%) Glomerulonephritis, n (%)2 (2.9%)4 (6%)6 (4.4%) Polycystic kidney disease, n (%)1 (1.4%)2 (3%)3 (2.2%) Other etiologies, n (%)3 (4.3%)6 (9%)9 (6.6%)Comorbid illnesses Diabetes mellitus, n (%)54 (78.3%)47 (70.1%)101 (74.3%) Cardiovascular disease, n (%)43 (62.3%)30 (44.8%)73 (53.7%) Hospitalized heart failure, n (%)21 (30.4%)16 (23.9%)37 (27.2%) Myocardial infarction, n (%)17 (24.6%)17 (25.4%)34 (25%) Coronary revascularization, n (%)21 (30.4%)15 (22.4%)36 (26.5%) Pacemaker or defibrillator, n (%)7 (10.1%)6 (9%)13 (9.6%) Stroke, n (%)9 (13%)6 (9%)15 (11%) Peripheral vascular disease, n (%)12 (17.4%)7 (10.4%)19 (14%) Hospitalized infectious disease, n (%)34 (49.3%)22 (32.8%)56 (41.2%) Skin (e.g., cellulitis), n (%)11 (15.9%)4 (6%)15 (11%) Bone (e.g., pyogenic arthritis, osteomyelitis), n (%)6 (8.7%)3 (4.5%)9 (6.6%) Lung (e.g., pneumonia), n (%)16 (23.2%)5 (7.5%)21 (15.4%) Sepsis, n (%)6 (8.7%)1 (1.5%)7 (5.1%) Urinary tract infections, n (%)7 (10.1%)5 (7.5%)12 (8.8%) Other infections, n (%)3 (4.3%)4 (6%)7 (5.1%) Gastrointestinal bleeding, n (%)8 (11.6%)3 (4.5%)11 (8.1%) Past RBC transfusion, n (%)13 (18.8%)12 (17.9%)25 (18.4%)Smoking, n (%) Never smoker, n (%)13 (18.8%)17 (25.4%)30 (22.1%) Past smoker, n (%)44 (63.8%)39 (58.2%)83 (61%) Active smoker, n (%)12 (17.4%)11 (16.4%)23 (16.9%)Medication use ACE inhibitor or ARB use, n (%)45 (65.2%)43 (64.2%)88 (64.7%) Statin use, n (%)48 (69.6%)44 (65.7%)92 (67.6%) Antiplatelet agent use, n (%)47 (68.1%)35 (52.2%)82 (60.3%) Erythropoietin agent use, n (%)5 (7.2%)6 (9%)11 (8.1%)Blood pressure Seated clinic systolic BP (mm Hg)131.4±21.9129±18.5130.2±20.3 Seated clinic diastolic BP (mm Hg)63.2±13.465.7±12.464.4±13Proteinuria stratum High proteinuria stratum (≥3 g/g)9 (13%)9 (13.4%)18 (13.2%) Low proteinuria stratum (<3 g/g)60 (87%)58 (86.6%)118 (86.8%)Laboratory parameters Hemoglobin (g/dl)10.5±110.7±110.6±1 Transferrin saturation (%)17.3±6.717.4±5.117.3±5.9 Serum ferritin (ng/ml)133±155173±138153±148 Serum albumin (g/dl)3.5±0.53.5±0.63.5±0.5 Estimated GFR (ml/min per 1.73 m2)34.7±1034.3±10.234.5±10 Log urinary protein/creatinine (mg/mg)-0.9±1.4-0.6±1.5-0.7±1.4Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; GFR, glomerular filtration rate; RBC, red blood cell. Open table in a new tab Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; GFR, glomerular filtration rate; RBC, red blood cell. Figure 1a shows hemoglobin levels at baseline and over time in all participants. At baseline, mean hemoglobin was 10.5 g/dl in the oral iron group and 10.7 g/dl in the IV iron group. Hemoglobin levels improved over time in both groups, and no statistically significant difference between mean levels in the treatment groups was noted during follow-up. Changes in transferrin saturation, total iron binding capacity, and serum ferritin are shown in Figure 1b–d. Serum ferritin concentration was significantly higher in the IV iron group only from baseline to 6 months. Beyond the first 8 weeks of repletion therapy, IV iron administration was given to two subjects in the oral iron group (doses of 250 and 1000 mg), of which one was given during hospitalization. In contrast, 9 subjects in the IV iron group received additional IV iron at a median dose of 1729 mg (interquartile range 838–2000 mg). In comparison, oral iron was prescribed after the 8-week randomized treatment period to 7 subjects in the IV iron group for median of 20 days (interquartile range 12.3–20) and beyond the first 8 weeks to 36 subjects for a median of 60 days (interquartile range 30–to 90) (P-value for difference in medians=0.001). The average erythropoiesis-stimulating agent (ESA) use over the course of 2 years was similar in the two groups. In the oral iron group, 22 subjects required ESA for an average of 61 weeks (s.d. 39) with a geometric mean cumulative dose of darbepoetin of 483 μg. In the IV iron group, 16 subjects required ESA for an average of 54 weeks (s.d. 41) with a geometric mean cumulative dose of darbepoetin of 614 μg. In each group, 12 study participants received blood transfusions. Of those who needed packed red blood cell transfusions, the mean number of units needed over 2 years was 5.3 (range 2–20 units) in the oral group and 3.5 (range 1–7) in the IV group (t=0.99, P=0.3). The trial was stopped early on the unanimous recommendation of the data and safety monitoring board based on an increase in the serious adverse event rate in participants assigned to IV iron treatment compared with oral iron therapy and little difference in mGFR between treatment groups. Given the persisting signal of safety, but little chance of finding the projected difference in measured GFR between groups, they unanimously recommended termination of the trial. Figure 2a shows the modeled iothalamate mGFR slopes in the two groups adjusted for baseline log urinary protein/creatinine ratio. Iothalamate GFR declined similarly over time in both groups (oral iron -3.6 ml/min per 1.73 m2 per year, IV iron –4.0 ml/min1.73 m2 per year, and between-group difference -0.35 ml/min per 1.73 m2 per year; 95% confidence interval (CI) -2.9 to 2.3, P=0.79). After additional adjustment for age, sex, black race, angiotensin-converting enzyme/angiotensin receptor blocker use, and cardiovascular disease, the rate of change in GFR became more similar between groups (oral iron -3.8 ml/min per 1.73 m2 per year, IV iron –3.9 ml/min per 1.73 m2 per year, and between-group difference -0.11 ml/min per 1.73 m2 per year; 95% CI -2.7 to 2.5, P=0.94; Figure 2b). The small baseline difference in proteinuria was not statistically significant. There was significant increase in proteinuria over time (P=0.04) in both treatment groups, but there was no significant difference between groups (Supplementary Figure S2 online). None of the domains of the KDQOL Questionnaire demonstrated any significant change over time or a significant interaction between treatment groups over time (Figure 3a–d). Table 2 shows the serious adverse events between groups over the course of the trial. There were six deaths in the IV group and four in the oral iron group. A total of 104.5 patient-years (PY) of follow-up were obtained in the oral iron treatment group and 101 PY of follow up in the IV iron treatment group. Serious adverse events in the oral iron group occurred in 40 subjects who had 176 events (168.4/100 PY); in the IV iron group they occurred in 37 subjects who had 201 events (199/100 PY), unadjusted incidence rate ratio (IRR) 1.18 (95% CI 0.97–1.45, P=0.106). Adjusted IRR was 1.60 (1.28–2.00), P<0.0001.Table 2Serious adverse events reported following randomizationOral iron (n=69)IV iron (n=67)Event typeSubjects (n)Events (n)Incidence rate (events/100 PY)Subjects (n)Events (n)Incidence rate (events/100 PY)Incidence rate ratio, IV/oral (95% CI)PAdjusted incidence rate ratio, IV/oral (95% CI)POverall SAEs40176168.4372011991.18 (0.97–1.45)0.1061.60 (1.28–2.00)<0.0001Infections112725.8193736.61.42 (0.86–2.33)0.1682.12 (1.24–3.64)0.006 Skin665.771110.91.90 (0.70–5.13)>0.23.79 (1.32–10.87)0.013 Bone276.73440.59 (0.17–2.02)>0.2 Lung443.881110.92.85 (0.91–8.94)0.0734.35 (1.23–15.39)0.022 UTI354.8354.91.03 (0.30–3.57)>0.22.37 (0.60–9.34)>0.2 Sepsis121.9554.92.59 (0.50–13.33)>0.2122.15 (0.89–16819.84)0.056 Other232.91110.34 (0.04–3.32)>0.2Cardiovascular193634.4175554.41.58 (1.04–2.41)0.033*2.51 (1.56–4.04)<0.001 CHF91514.392827.71.93 (1.03–3.62)0.040*2.07 (1.04–4.11)0.038 Angina221.92221.03 (0.15–7.35)>0.2 MI898.6898.91.03 (0.41–2.61)>0.21.25 (0.41–3.82)>0.2 Stroke0002222.0e+07 (0.00 -.)>0.2 Arrhythmia443.8454.91.29 (0.35–4.82)>0.2 PVD121.92331.55 (0.26–9.29)>0.2 Other443.8565.91.55 (0.44–5.50)>0.2Renal182927.7142827.71.00 (0.59–1.68)>0.21.39 (0.78–2.47)>0.2 AKI152221122120.80.99 (0.54–1.80)>0.2Hyperkalemia565.72440.69 (0.19–2.44)>0.2 Other1113333.10 (0.32–29.84)>0.2Cancer related443.8487.92.07 (0.62–6.87)>0.2 Other316966256160.40.91 (0.65–1.29)>0.2PRBC transfusion121716.3121918.81.16 (0.60–2.22)>0.2 GI bleed576.7000NANAHyperglycemia1112222.07 (0.19–22.82)>0.2Hypoglycemia354.8000NANADiabetic retinopathy121.9154.92.59 (0.50–13.33)>0.2Hypertensive crisis111354.95.17 (0.60–44.28)0.134Urinary retention232.92331.03 (0.21–5.13)>0.2Miscellaneous213331.6202726.70.85 (0.51–1.41)>0.2ESRD776.7665.90.89 (0.30––2.64)>0.21.04 (0.25–4.24)>0.2Death443.8665.91.55 (0.44–5.50)>0.21.60 (0.28–9.07)>0.2 CV related221.92221.03 (0.15–7.35)>0.2 Non-CV related221.94442.07 (0.38–11.30)>0.2Abbreviations: AKI, acute kidney injury; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; ESRD, end-stage renal disease; GI, gastrointestinal; IV, intravenous; MI, myocardial infarction; NA, not available; SAE, serious adverse event; PRBC, packed red blood cell; PVD, peripheral vascular disease; PY, patient-years; UTI, urinary tract infection.Oral iron exposure: 104.5 PY, and IV iron exposure: 101 PY. Adjustments for overall serious adverse events, cardiovascular events, renal events, AKI, hyperkalemia, and ESRD, death: age, sex, black race, stratum of proteinuria, baseline estimated glomerular filtration rate (GFR), diabetes, cardiovascular disease, tobacco use, systolic blood pressure (BP), statin use, antiplatelet therapy, angiotensin-converting enzyme (ACE) or angiotensin receptor blocker (ARB) use. Adjustments for CHF events: all the above adjustments except cardiovascular disease replaced by history of hospitalization for CHF. Adjustments for MI events: all the above adjustments except cardiovascular disease replaced by history of MI. Adjustments for infection events: all the above adjustments except dropped systolic BP, statin use, antiplatelet therapy, ACE or ARB use, and added history of hospitalized infection. Adjustments for skin infection events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized cellulitis. Adjustments for lung infection events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized pneumonia. Adjustments for urinary infection events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized UTI. Adjustments for sepsis events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized sepsis. Open table in a new tab Abbreviations: AKI, acute kidney injury; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; ESRD, end-stage renal disease; GI, gastrointestinal; IV, intravenous; MI, myocardial infarction; NA, not available; SAE, serious adverse event; PRBC, packed red blood cell; PVD, peripheral vascular disease; PY, patient-years; UTI, urinary tract infection. Oral iron exposure: 104.5 PY, and IV iron exposure: 101 PY. Adjustments for overall serious adverse events, cardiovascular events, renal events, AKI, hyperkalemia, and ESRD, death: age, sex, black race, stratum of proteinuria, baseline estimated glomerular filtration rate (GFR), diabetes, cardiovascular disease, tobacco use, systolic blood pressure (BP), statin use, antiplatelet therapy, angiotensin-converting enzyme (ACE) or angiotensin receptor blocker (ARB) use. Adjustments for CHF events: all the above adjustments except cardiovascular disease replaced by history of hospitalization for CHF. Adjustments for MI events: all the above adjustments except cardiovascular disease replaced by history of MI. Adjustments for infection events: all the above adjustments except dropped systolic BP, statin use, antiplatelet therapy, ACE or ARB use, and added history of hospitalized infection. Adjustments for skin infection events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized cellulitis. Adjustments for lung infection events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized pneumonia. Adjustments for urinary infection events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized UTI. Adjustments for sepsis events: all the adjustments for infection except that history of hospitalized infection replaced by prior history of hospitalized sepsis. Serious adverse events due to infections in the oral iron group occurred 27 times in 11 subjects (25.8/100 PY); in the IV iron group they occurred 37 times in 19 subjects (36.6/100 PY; IRR 1.42 (95% CI 0.86–2.33, P=0.17). Adjusted IRR was 2.12 (1.24–3.64), P<0.006. Compared with the oral iron group, the incidence of lung and skin infections were increased between three- and fourfold in the IV iron group. Cardiovascular events in the oral iron group occurred 36 times in 19 subjects (34.4/100 PY); in the IV iron group they occurred 55 times in 17 subjects (54.4/100 PY; IRR 1.58 (95% CI 1.04–2.41, P=0.033). Adjusted IRR was 2.51 (1.56–4.04), P<0.001. Compared with the oral iron group, the incidence of hospitalized heart failure was increased approximately twofold in the IV iron group. Supplementary Figures S3–S5 online show that the distribution of the events was such that it was not one or two subjects in one group who influenced the outcomes. Overall, gastrointestinal adverse events particularly diarrhea were more common among participants randomized to oral iron (Supplementary Table S1, Supplementary Appendix online). On the other hand, gout was more frequent among those randomized to IV iron. Among anemic patients with iron deficiency and CKD enrolled in the REVOKE trial IV iron therapy, we failed to confirm that IV iron accelerates the decline in kidney function. However, IV iron was associated with an increased frequency of overall serious adverse events as well as cardiovascular and infectious complications. Specifically, IV iron administration was also associated with an increased incidence of the hospitalizations due to congestive heart failure, pneumonias, and serious skin infections (requiring administration of antibiotics in the hospital) that became apparent after adjustment for the more favorable clinical and demographic characteristics at baseline among participants assigned to IV iron therapy (younger age, lower prevalence of cardiovascular disease, and hospitalized infections). Treatment with either oral or IV iron-repletion therapy produced statistically and clinically significant improvements in hemoglobin that were sustained over the 24 months of the trial. In a meta-analysis comparing randomized trials of oral with IV iron on hemoglobin response among patients with CKD not on dialysis, Rozen-Zvi et al.20.Rozen-Zvi B. Gafter-Gvili A. Paul M. et al.Intravenous versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis.Am J Kidney Dis. 2008; 52: 897-906Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar reported six studies. Five of these six trials were of short term, 1–3 months, and compared with oral iron, the mean increase in hemoglobin with IV iron was 0.31 (95% CI 0.09–0.53) g/dl. However, one of the studies included in this meta-analysis was 6 months long and had a mean decline in hemoglobin of 0.52 g/dl associated with IV iron administration.21.Stoves J. Inglis H. Newstead C.G. A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin.Nephrol Dial Transplant. 2001; 16: 967-974Crossref PubMed Scopus (88) Google Scholar In the largest randomized clinical trial comparing IV with oral iron in iron-deficient anemic patients with CKD, the Ferinject assessment in patients with Iron deficiency anemia and Non-Dialysis-dependent Chronic Kidney Disease (FIND-CKD) investigators randomized 626 patients in 193 centers in a 1:1:2 ratio to ferric carboxymaltose targeting ferritin to high-level (400–600 ng/ml), lower-level (100–200 ng/ml), or oral iron with the primary end point of time to initiation of other anemia management (ESA, other iron therapy, or blood transfusion) or hemoglobin trigger of two consecutive values of <10 g/dl during weeks 8–52. The investigators reported the mean change in hemoglobin from baseline to 52 weeks as 1.0 g/dl in oral iron group, 0.9 g/dl when IV ferric carboxymaltose targeted ferritin to 100–200 ng/ml, and 1.4 g/dl (P=0.26) when IV ferric carboxymaltose targeted ferritin to 400–600 ng/ml (P=0.014).22.Macdougall I.C. Bock A.H. Carrera F. et al.FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia.Nephrol Dial Transplant. 2014; 29: 2075-2084Crossref PubMed Scopus (183) Google Scholar Although statistically significant, the difference in hemoglobin of 0.4 g/dl between oral iron and high-dose IV iron observed in that study should be interpreted cautiously because the oral ferrous sulfate administration was only 100 mg twice daily that is much below the recommended intake of ferrous sulfate 325 mg three times daily used in our trial. Given the short duration of most of the clinical trials comparing oral with IV administration of iron, the long-term safety of these modes of administration of supplemental iron could not be assessed. Accordingly, guidelines have no recommendation on the preferred mode of iron administration in such patients.19.Kidney Disease Improving Global Outcomes (KDIGO) Anemia Work Group KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (668) Google Scholar We showed that compared with oral iron-based therapy, IV iron therapy was associated with greater risk of infections and cardiovascular complications. Although assignment to the IV iron treatment group resulted in greater increments in both transferrin saturation and serum ferritin concentration, suggesting a better repletion of iron stores, there was little difference in mean hemoglobin increments in the long term. Overall, there was an increase in proteinuria noted, but between-group differences over time in baseline proteinuria were not observed. These findings confirm no increase in basal level of proteinuria over several weeks among patients receiving IV iron.16.Agarwal R. Leehey D.J. Olsen S.M. et al.Proteinuria induced by parenteral iron in chronic kidney disease—a comparative randomized controlled trial.Clin J Am Soc Nephrol. 2011; 6: 114-121Crossref PubMed Scopus (25) Google Scholar The adverse events observed in our randomized trial are biologically plausible. Iron promotes growth of even common bacteria such as Staphylococcus epidermidis.23.Parkkinen J. von Bonsdorff L. Peltonen S. et al.Cataly" @default.
• W1571358690 created "2016-06-24" @default.
• W1571358690 creator A5037535062 @default.
• W1571358690 creator A5040913447 @default.
• W1571358690 creator A5051708137 @default.
• W1571358690 date "2015-10-01" @default.
• W1571358690 modified "2023-10-14" @default.
• W1571358690 title "A randomized trial of intravenous and oral iron in chronic kidney disease" @default.
• W1571358690 cites W1752039509 @default.
• W1571358690 cites W1964685535 @default.
• W1571358690 cites W1975380578 @default.
• W1571358690 cites W1988814980 @default.
• W1571358690 cites W1989893606 @default.
• W1571358690 cites W1997223215 @default.
• W1571358690 cites W2017933369 @default.
• W1571358690 cites W2018037599 @default.
• W1571358690 cites W2028265881 @default.
• W1571358690 cites W2034019394 @default.
• W1571358690 cites W2046644339 @default.
• W1571358690 cites W2058411952 @default.
• W1571358690 cites W2067573387 @default.
• W1571358690 cites W2073742622 @default.
• W1571358690 cites W2088374227 @default.
• W1571358690 cites W2091148694 @default.
• W1571358690 cites W2111648863 @default.
• W1571358690 cites W2112038098 @default.
• W1571358690 cites W2115208217 @default.
• W1571358690 cites W2116948290 @default.
• W1571358690 cites W2120601666 @default.
• W1571358690 cites W2123173784 @default.
• W1571358690 cites W2131019172 @default.
• W1571358690 cites W2132857214 @default.
• W1571358690 cites W2133914089 @default.
• W1571358690 cites W2134252848 @default.
• W1571358690 cites W2135083569 @default.
• W1571358690 cites W2138999309 @default.
• W1571358690 cites W2142471162 @default.
• W1571358690 cites W2148669301 @default.
• W1571358690 cites W2157416061 @default.
• W1571358690 cites W2163535392 @default.
• W1571358690 cites W2409896571 @default.
• W1571358690 cites W4239234884 @default.
• W1571358690 doi "https://doi.org/10.1038/ki.2015.163" @default.
• W1571358690 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4589436" @default.
• W1571358690 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26083656" @default.
• W1571358690 hasPublicationYear "2015" @default.
• W1571358690 type Work @default.
• W1571358690 sameAs 1571358690 @default.
• W1571358690 citedByCount "149" @default.
• W1571358690 countsByYear W15713586902015 @default.
• W1571358690 countsByYear W15713586902016 @default.
• W1571358690 countsByYear W15713586902017 @default.
• W1571358690 countsByYear W15713586902018 @default.
• W1571358690 countsByYear W15713586902019 @default.
• W1571358690 countsByYear W15713586902020 @default.
• W1571358690 countsByYear W15713586902021 @default.
• W1571358690 countsByYear W15713586902022 @default.
• W1571358690 countsByYear W15713586902023 @default.
• W1571358690 crossrefType "journal-article" @default.
• W1571358690 hasAuthorship W1571358690A5037535062 @default.
• W1571358690 hasAuthorship W1571358690A5040913447 @default.
• W1571358690 hasAuthorship W1571358690A5051708137 @default.
• W1571358690 hasBestOaLocation W15713586901 @default.
• W1571358690 hasConcept C126322002 @default.
• W1571358690 hasConcept C168563851 @default.
• W1571358690 hasConcept C177713679 @default.
• W1571358690 hasConcept C2777417653 @default.
• W1571358690 hasConcept C2778248108 @default.
• W1571358690 hasConcept C2778653478 @default.
• W1571358690 hasConcept C2779134260 @default.
• W1571358690 hasConcept C3020614022 @default.
• W1571358690 hasConcept C71924100 @default.
• W1571358690 hasConceptScore W1571358690C126322002 @default.
• W1571358690 hasConceptScore W1571358690C168563851 @default.
• W1571358690 hasConceptScore W1571358690C177713679 @default.
• W1571358690 hasConceptScore W1571358690C2777417653 @default.
• W1571358690 hasConceptScore W1571358690C2778248108 @default.
• W1571358690 hasConceptScore W1571358690C2778653478 @default.
• W1571358690 hasConceptScore W1571358690C2779134260 @default.
• W1571358690 hasConceptScore W1571358690C3020614022 @default.
• W1571358690 hasConceptScore W1571358690C71924100 @default.
• W1571358690 hasIssue "4" @default.
• W1571358690 hasLocation W15713586901 @default.
• W1571358690 hasLocation W15713586902 @default.
• W1571358690 hasLocation W15713586903 @default.
• W1571358690 hasLocation W15713586904 @default.
• W1571358690 hasLocation W15713586905 @default.
• W1571358690 hasOpenAccess W1571358690 @default.
• W1571358690 hasPrimaryLocation W15713586901 @default.
• W1571358690 hasRelatedWork W1540807578 @default.
• W1571358690 hasRelatedWork W1588968920 @default.
• W1571358690 hasRelatedWork W2016976166 @default.
• W1571358690 hasRelatedWork W2114905932 @default.
• W1571358690 hasRelatedWork W2471594942 @default.
• W1571358690 hasRelatedWork W2554424493 @default.
• W1571358690 hasRelatedWork W2888428943 @default.
• W1571358690 hasRelatedWork W2919291229 @default.
• W1571358690 hasRelatedWork W4233819913 @default.

• next