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Eritropoyetina humana recombinante versus placebo o ningún tratamiento para la anemia de la enfermedad renal crónica en pacientes que no requieren diálisis

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References

References to studies included in this review

Abraham 1990 {published data only}

Abraham PA, Opsahl JA, Rachael KM, Asinger R, Halstenson CE. Renal function during erythropoietin therapy for anemia in predialysis chronic renal failure patients. American Journal of Nephrology 1990;10(2):128‐36. [MEDLINE: 2349956]
Opsahl JA, Halstenson CE, Rachael KM, Abraham PA. Recombinant‐human erythropoietin (EPO) in chronic renal failure (CRF): no adverse effect on renal hemodynamics or progression of disease [abstract]. Kidney International 1989;35(1):198. [CENTRAL: CN‐00766225]

Akizawa 1993 {published data only}

Akizawa T, Koshikawa S. Effect of rHuEPO on progression of renal disease [abstract]. 12th International Congress of Nephrology; 1993 June 13‐18; Jerusalem, Israel. 1993:300. [CENTRAL: CN‐00764752]

Brown 1995 {published data only}

Brown CD, Zhao ZH, Thomas LL, Friedman EA. Erythropoietin delays the onset of uremia in anemic azotemic diabetic predialysis patients [abstract]. Journal of the American Society of Nephrology 1995;6(3):447A. [MEDLINE: CN‐00483340]

Clyne 1992 {published data only}

Clyne N, Jogestrand T. Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron 1992;60(4):390‐6. [MEDLINE: 1584314]

Eschbach 1989 {published data only}

Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. New England Journal of Medicine 1989;321(3):158‐63. [MEDLINE: 2747747]

Ganguli 2003 {published data only}

Ganguli A, Singh NP, Ahuja N. A comparative study of nandrolone decanoate and erythropoietin on albumin levels, quality of life, and progression of renal disease in Indian predialysis CKD patients [abstract no: W455]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):692. [CENTRAL: CN‐00653811]
Ganguli A, Singh NP, Singh T, Agarwal SK, Neeraj A. Nandrolone decanoate is equiefacious to erythropoietin in correcting anemia and quality of life in predialysis chronic kidney disease patients [abstract no: 137]. Journal of the Association of Physicians of India 2003;51(Dec):1188. [CENTRAL: CN‐00765715]
Singh NP, Anirban G, Singh T, Agarwal SK, Neera A. Long term effects of anemia correction on progression of renal disease and cognitive function using erythropoietin and androgenic steroids [abstract no: 136]. Journal of the Association of Physicians of India 2003;51(Dec):1188. [CENTRAL: CN‐00783567]
Singh NP, Ganguli A, Singh T. A comparative study of nandrolone decanoate versus recombinant human erythropoietin on anemia in Indian predialysis chronic kidney disease patients [abstract no: W456]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):692‐3. [CENTRAL: CN‐00447760]

Kim 2006e {published data only}

Kim BS, Do JY, Kim DJ, Kim Y, Kim C, Park S, et al. Renal outcome of CKD patients with predialysis erythropoietin therapy: a prospective, randomized, multicenter clinical study [abstract no: TH‐FC057]. Journal of the American Society of Nephrology 2006;17(Abstracts):13A. [CENTRAL: CN‐00766279]

Kleinman 1989 {published data only}

Kleinman KS, Schweitzer SU. Human recombinant erythropoietin (rHuEPO) treatment of severe anemia associated with progressive renal failure may delay the need to initiate regular dialytic therapy [abstract]. Kidney International 1990;37:240. [CENTRAL: CN‐00626057]
Kleinman KS, Schweitzer SU, Perdue ST, Abels RI. The use of recombinant human erythropoietin in the correction of anemia in pre‐dialysis patients and its effects on renal function: a double blind placebo controlled trial [abstract]. Kidney International 1989;35(1):229. [CENTRAL: CN‐00636148]
Kleinman KS, Schweitzer SU, Perdue ST, Bleifer KH, Abels RI. The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double‐blind, placebo‐controlled trial. American Journal of Kidney Diseases 1989;14(6):486‐95. [MEDLINE: 2688405]

Kristal 2008 {published data only}

Kristal B, Shurtz‐Swirski R, Tanhilevski O, Shapiro G, Shkolnik G, Chezar J, et al. Epoetin‐alpha: preserving kidney function via attenuation of polymorphonuclear leukocyte priming. Israel Medical Association Journal ‐ Imaj 2008;10(4):266‐72. [MEDLINE: 18548979]

Kuriyama 1997 {published data only}

Kuriyama S, Tomonari H, Hashimoto T, Kawaguchi Y, Sakai O. Reversal of anemia by EPO therapy retards the progression of chronic renal failure in non‐diabetic pre‐dialysis patients [abstract]. Nephrology 1997;3(Suppl 1):S506. [CENTRAL: CN‐00461123]
Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997;77(2):176‐85. [MEDLINE: 9346384]

Lim 1989 {published data only}

Lim VS, DeGowin RL, Zavala D, Kirchner PT, Abels R, Perry P, et al. Recombinant human erythropoietin treatment in pre‐dialysis patients. A double‐blind placebo‐controlled trial. Annals of Internal Medicine 1989;110(2):108‐14. [MEDLINE: 2909202]

Roth 1994 {published data only}

Benz R, Teehan B, Roth D, Buckalew V, Freedman B, Hatch F, et al. Renal function and quality of life (QOL) studies in anemic, pre‐dialysis chronic renal failure (CRF) patients receiving recombinant human erythropoietin (r‐HuEPO): results of a multi‐center trial [abstract]. 12th International Congress of Nephrology; 1993 June 13‐18; Jerusalem, Israel. 1993:316. [CENTRAL: CN‐00602029]
Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al. Health‐related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. American Journal of Kidney Diseases 1995;25(4):548‐54. [MEDLINE: 7702049]
Roth D, Smith RD, Schulman G, Steinman TI, Hatch FE, Rudnick MR, et al. Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. American Journal of Kidney Diseases 1994;24(5):777‐84. [MEDLINE: 7977319]

Stone 1988 {published data only}

Stone WJ, Graber SE, Krantz SB, Dessypris EN, O'Neil VL, Olsen NJ, et al. Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebo‐controlled trial. American Journal of Medical Sciences 1988;296(3):171‐9. [MEDLINE: 3177433]

Teehan 1989 {published data only}

Teehan BP, Sigler MH, Brown JM, Benz RL, Gilgore GS, Schleifer CR, et al. Hematologic and physiologic studies during correction of anaemia with recombinant human erythropoietin in predialysis patients. Transplantation Proceedings 1989;21 Suppl(2):63‐6. [EMBASE: 1990284570]

Teehan 1991 {published data only}

Double‐blind, placebo‐controlled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients. The US Recombinant Human Erythropoietin Predialysis Study Group.[Erratum appears in Am J Kidney Dis 1991 Sep;18(3):420]. American Journal of Kidney Diseases 1991;18(1):50‐9. [MEDLINE: 2063855]

Teplan 2001b {published data only}

Teplan V, Schuck O, Knotek A, Hojny J, Horackova M. Ketoacids and recombinant human erythro‐poietin may influence progression of chronic renal insufficiency: Czech multicentre study [abstract]. Nephrology Dialysis Transplantation 2001;16(6):A96. [CENTRAL: CN‐00447973]

Teplan 2003 {published data only}

Teplan V, Schuck O, Knotek A, Hajny J, Horackova M, Kvapil M, Czech multicenter study. Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low‐protein diet: Czech multicenter study. American Journal of Kidney Diseases 2003;41(3 Suppl 1):S26‐30. [MEDLINE: 12612947]
Teplan V, Schuck O, Knotek A, Hajny J, Surel S. Metabolic effect of erythropoietin and keto acids in CRF: Czech multicentre study [abstract]. Nutrition 2003;19(4):399.
Teplan V, Schuck O, Poledne R, Mengerova O. The influence of erythropoietin (r‐Hu EPO) and keto amino acids (KA) on lipid metabolism and renal function tests in chronic renal failure (CRF) [abstract no: A3094]. Journal of the American Society of Nephrology 1996;7(9):1865. [CENTRAL: CN‐00766750]
Teplan V, Schuck O, et al. Erythropoietin (r‐Hu EPO) and keto amino acids (KA): an effect on lipid metabolism in predialysis [abstract]. Nephrology Dialysis Transplantation 1996;11(6):A263. [CENTRAL: CN‐00261317]

Wang 2004b {published data only}

Wang AY, Chook P, Chow K, Sanderson J, Li PK, Lui S, et al. A prospective randomized study to evaluate erythropoietin treatment as a novel strategy for improving vascular dysfunction and atherosclerosis prevention in chronic renal failure. [abstract no: SA‐FC104]. Journal of the American Society of Nephrology 2004;15(Oct):43A. [CENTRAL: CN‐00763755]

Watson 1990 {published data only}

Watson A, Gimenez L, Walser M, Cotton S, Spivak J. A prospective double‐blind study of subcutaneous recombinant‐human erythropoietin in predialysis renal failure. Journal of Clinical Pharmacology 1989;29:856.
Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL. Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. American Journal of Medicine 1990;89(4):432‐5. [MEDLINE: 2220877]

References to studies excluded from this review

Brown 1988 {published data only}

Brown CD, Kieran M, Dosunmu BV, Zhao Z, Larson RH, Friedman EA. Raised hematocrit (HCT) persists six‐weeks after stopping treatment with human recombinant erythropoietin (r‐HuEPO) in azotemic anemic patients [abstract]. Kidney International 1988;33(1):184. [CENTRAL: CN‐00602117]

CREATE Study 2001 {published data only}

Clyne N, Drueke T, Eckardt K, Locatelli F, Macdougall I, Tsakiris D. Quality of life assessment in the 'cardiovascular risk reduction by early anaemia treatment with epoetin beta' (CREATE) study [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):155‐6. [CENTRAL: CN‐00444859]
Clyne N, Drueke TB, Eckardt K, Locatelli F, Macdougall IC, Tsakiris D, et al. Diagnostic value of NT‐proBNP in CKD patients: baseline and 6‐month data from the CREATE Study [abstract no: F‐PO320]. Journal of the American Society of Nephrology 2004;15(Oct):136A. [CENTRAL: CN‐00550685]
Clyne N, Macdougall I, Bilous R, Ritz E, CREATE Study Group, ACORD Study Group. Haemoglobin control with epoetin beta: results from the Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta (CREATE) and Anaemia Correction in Diabetes (ACORD) studies [abstract no: SP457]. Nephrology Dialysis Transplantation 2006;21(Suppl 4):iv169. [CENTRAL: CN‐00583337]
Drueke T, Clyne N, Eckardt K, Locatelli F, Macdougall I, Tsakiris D, et al. Diagnostic value of NT‐proBNP and cardiac troponin T in chronic kidney disease patients: correlation with baseline characteristics in the CREATE study [abstract no: P210]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004:85. [CENTRAL: CN‐00509163]
Drueke T, Clyne N, Eckardt K, Locatelli F, Macdougall I, Tsakiris D, et al. Homocysteine as a cardiovascular risk marker in patients with chronic kidney disease: baseline data and risk profiles from the CREATE study [abstract no: SP207]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004:84. [CENTRAL: CN‐00509164]
Drueke T, Clyne N, Eckardt K, Locatelli F, Macdougall IC, Tsakiris D, et al. Homocysteine as a cardiovascular risk marker in patients with CKD: baseline and 6‐month data from the CREATE Study [abstract no: F‐PO335]. Journal of the American Society of Nephrology 2004;15(Oct):139A‐40A. [CENTRAL: CN‐00550688]
Drueke T, Clyne N, Eckardt KU, Locatelli F, Macdougell I, Tsakiris D, et al. Baseline characteristics of chronic renal failure patients not yet receiving renal replacement therapy enrolled in the CREATE study [abstract no: T135]. Nephrology Dialysis Transplantation 2002;17(Suppl 12):227. [CENTRAL: CN‐00509165]
Drueke T, Locatelli F, Clyne N, Eckardt KU, Macdougall I, Tsakiris D. Cardiovascular disease (CVD) characteristics of chronic kidney disease (CKD) patients enrolled in the 'cardiovascular risk reduction by early anaemia treatment with epoetin beta' (CREATE) study [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):156. [CENTRAL: CN‐00520329]
Drueke TB, Clyne N, Eckardt KU, Locatelli F, Macdougall IC, Tsakiris D. Characteristics of chronic kidney disease (CKD) patients enrolled in the 'cardiovascular risk reduction by early anemia treatment with epoetin beta' (CREATE) study [abstract no: SU‐P025]. Journal of the American Society of Nephrology 2002;13(September, Program & Abstracts):520A. [CENTRAL: CN‐00445149]
Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New England Journal of Medicine 2006;355(20):2071‐84. [MEDLINE: 17108342]
Eckardt K, Clyne N, Drueke T, Locatelli F, Macdougall I, Tsakiris D, et al. Variables of left ventricular geometry and function in patients enrolled in the CREATE trial [abstract no: T136]. Nephrology Dialysis Transplantation 2002;17(Suppl 1):227. [CENTRAL: CN‐00583726]
Eckardt K, Macdougall I, Locatelli F, Tsakiris D, Clyne N, Drueke T. Effects of epoetin beta on left ventricular mass in patients with chronic kidney disease: echocardiographic results from the CREATE study [abstract no: TH‐FC172]. Journal of the American Society of Nephrology 2005;16:37A. [CENTRAL: CN‐00583370]
Eckardt KU, Clyne N, Drueke T, Locatelli F, Macdougall I, Tsakiris D. Left ventricular hypertrophy and associated variables in the 'cardiovascular risk reduction by early anaemia treatment with epoetin beta (CREATE) trial [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):155. [CENTRAL: CN‐00445194]
Eckardt KU, Scherhag A, Macdougall IC, Tsakiris D, Clyne N, Locatelli F, et al. Left ventricular geometry predicts cardiovascular outcomes associated with anemia correction in CKD. Journal of the American Society of Nephrology 2009;20(12):2651‐60. [MEDLINE: 19850955]
Eckardt KU, The Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) Trial. The CREATE trial‐‐building the evidence. Nephrology Dialysis Transplantation 2001;16 Suppl 2:16‐8. [MEDLINE: 11369844]
Locatelli F, Clyne N, Drueke T, Eckardt KU, Macdougall I, Tsakiris D, et al. Distribution of cardiovascular disease (CVD) across three geographical regions in patients with chronic renal failure (CRF) not yet receiving renal replacement therapy (RRT) enrolled in the CREATE study [abstract]. Nephrology Dialysis Transplantation 2002;17(Suppl 1):227‐8. [CENTRAL: CN‐00550716]
Locatelli F, Del Vecchio L, Pozzoni P. Anemia and cardiovascular risk: the lesson of the CREATE Trial. Journal of the American Society of Nephrology 2006;17(12 Suppl 3):S262‐6. [MEDLINE: 17130272]
Macdougall IC, Clyne N, Drueke TB, Eckardt K, Tsakiris D, Locatelli F, et al. Left ventricular hypertrophy and related variables in chronic kidney disease patients not receiving RRT enrolled in the cardiovascular risk reduction by early anemia treatment with epoetin beta (CREATE) study [abstract no: SU‐PO629]. Journal of the American Society of Nephrology 2003;14(Nov):672A. [CENTRAL: CN‐00550747]
Macdougall IC, Steering Committee of the CREATE trial, CREATE Study Group. CREATE: new strategies for early anaemia management in renal insufficiency. Nephrology Dialysis Transplantation 2003;18 Suppl 2:ii13‐6. [MEDLINE: 12819295]
Tsakiris D, Clyne N, Drueke T, Eckardt K, Macdougall I, Locatelli F, et al. Impaired quality of life in chronic kidney disease patients enrolled in the cardiovascular risk reduction by early anemia treatment with epoetin beta (CREATE) study [abstract no: SA‐PO723]. Journal of the American Society of Nephrology 2003;14(Nov):456A. [CENTRAL: CN‐00550393]

EPOCARES Study 2010 {published data only}

Emans ME, Braam B, Diepenbroek A, van der Putten K, Cramer MJ, Wielders JP, et al. Neutrophil gelatinase‐associated lipocalin (NGAL) in chronic cardiorenal failure is correlated with endogenous erythropoietin levels and decreases in response to low‐dose erythropoietin treatment. Kidney & Blood Pressure Research 2013;36(1):344‐54. [MEDLINE: 23235391]
Emans ME, van der PK, Velthuis BK, de Vries JJ, Cramer MJ, America YG, et al. Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging. BMC Cardiovascular Disorders 2012;12:76. [MEDLINE: 22989293]
Emans ME, van der PK, van Rooijen KL, Kraaijenhagen RJ, Swinkels D, van Solinge WW, et al. Determinants of red cell distribution width (RDW) in cardiorenal patients: RDW is not related to erythropoietin resistance. Journal of Cardiac Failure 2011;17(8):626‐33. [MEDLINE: 21807323]
Jie KE, Putten K, Wesseling S, Joles JA, Bergevoet MW, Pepers‐de Kort F, et al. Short‐term erythropoietin treatment does not substantially modulate monocyte transcriptomes of patients with combined heart and renal failure. PloS ONE [Electronic Resource] 2012;7(9):e41339. [MEDLINE: 22957013]
Jie KE, van der PK, Bergevoet MW, Doevendans PA, Gaillard CA, Braam B, et al. Short‐ and long‐term effects of erythropoietin treatment on endothelial progenitor cell levels in patients with cardiorenal syndrome. Heart 2011;97(1):60‐5. [MEDLINE: 21071558]
van der Putten K, Jie KE, Emans ME, Verhaar MC, Joles JA, Cramer MJ, et al. Erythropoietin treatment in patients with combined heart and renal failure: objectives and design of the EPOCARES study. Journal of Nephrology 2010;23(4):363‐8. [MEDLINE: 20383871]
van der Putten K, Jie KE, van den Broek D, Kraaijenhagen RJ, Laarakkers C, Swinkels DW, et al. Hepcidin‐25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients. European Journal of Heart Failure 2010;12(9):943‐50. [MEDLINE: 20601671]
van der Putten K, van den Broek D, van Rooijen KL, Kraaijenhagen RJ, Swinkels DW, Braam B, et al. Erythropoetin (EPO) induced decrease in hepcidin determines bone marrow response in patients with combined heart and renal failure [abstract no: SA‐PO2668]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):712A.

Frenken 1989 {published data only}

Frenken LA, Verberckmoes R, Michielsen P, Koene RA. Efficacy and tolerance of treatment with recombinant‐human erythropoietin in chronic renal failure (pre‐dialysis) patients. Nephrology Dialysis Transplantation 1989;4(9):782‐6. [MEDLINE: 2516609]
Frenken LA, Verberckmoes R, Sluiter HE, Schrijver G, Michielsen P, Koene RA. An open study of the safety and efficacy of multiple doses of recombinant human erythropoietin in end‐stage renal disease (predialysis) patients [abstract]. Nephrology Dialysis Transplantation 1988;3(4):495. [CENTRAL: CN‐00260377]
Frenken LA, Verberckmoes R, Sluiter HE, Schrijver G, Michielsen P, Koene RA. An open study of the safety and efficacy of multiple doses of recombinant‐human erythropoietin in end‐state renal disease (pre‐dialysis) patients [abstract]. Kidney International 1988;34(4):558. [CENTRAL: CN‐00644276]

Frenken 1992 {published data only}

Frenken LA, Wetzels JF, Sluiter HE, Koene RA. Evidence for renal vasodilation in pre‐dialysis patients during correction of anemia by erythropoietin. Kidney International 1992;41(2):384‐7. [MEDLINE: 1552711]

Furukawa 1992 {published data only}

Furukawa A, Numata A, Imagawa A, Kaifu Y, Sumikura T, Miyake H, et al. Study of recombinant human erythropoietin treatment on the anemia of predialysis patients. Nippon Jinzo Gakkai Shi [Japanese Journal of Nephrology] 1992;34(6):693‐700. [MEDLINE: 1479709]

Jabs 1994 {published data only}

Beeghly M, Jabs K, Johnson B, Tronick E, McCabe D, Alexander S, et al. Cognitive and adaptive function of children with end‐stage renal disease (ESRD): a report of the National Pediatric Recombinant Erythropoietin Study [abstract]. Journal of the American Society of Nephrology 1992;3(3):280. [CENTRAL: CN‐00460367]
Jabs K, Alexander S, McCabe D, Lerner G, Harmon W. Primary results from the U.S. multicenter pediatric recombinant erythropoietin (EPO) study [abstract]. Journal of the American Society of Nephrology 1994;5(3):456. [CENTRAL: CN‐00583204]
Van Dop C, Jabs KL, Alexander SA, Salusky IB, McCabe D. Correction of anemia does not improve growth or endocrine function in children with ESRD: a report from the U.S. multicenter pediatric recombinant erythropoietin (EPO) study [abstract]. Journal of the American Society of Nephrology 1995;6(3):407. [CENTRAL: CN‐00486268]

Koene 1990 {published data only (unpublished sought but not used)}

Koene R, Frenken L. Does treatment of predialysis patients with recombinant human erythropoietin compromise renal function?. Nefrologia 1990;10 Suppl(2):131‐6.
Koene RA, Frenken LA. Does treatment of predialysis patients with recombinant human erythropoietin compromise renal function?. Contributions to Nephrology 1990;87:105‐12. [MEDLINE: 2093536]

Macdougall 2007 {published data only}

Bennett‐Jones D. Use of epoetin alpha in the treatment in anaemia in predialysis patients. www.nihr.ac.uk/Profile/Pages/NRRResults.aspx?publication_id=N0055116759(last accessed July 2014).
Kwan JT, Temple M, Macdougall I. Is early treatment of anemia with epoetin‐alfa beneficial to predialysis renal patients? An UK multi‐centre study [abstract: SU‐PO057]. Journal of the American Society of Nephrology 2004;15(Oct):545A. [CENTRAL: CN‐00765503]
Macdougall IC, Kwan J, Temple RM, EPO‐GBR‐2 Investigator Study Group. UK multicentre randomised controlled study of epoetin alfa in early renal insufficiency (ERI) ‐ a 12‐month interim analysis [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):395A. [CENTRAL: CN‐00766947]
Macdougall IC, Temple RM, Kwan JT. Is early treatment of anaemia with epoetin‐alpha beneficial to pre‐dialysis chronic kidney disease patients? Results of a multicentre, open‐label, prospective, randomized, comparative group trial. Nephrology Dialysis Transplantation 2007;22(3):784‐93. [MEDLINE: 16968726]

Marcas 2003 {published data only}

Marcas L, Martinez‐Vea A, Bardaji A, Gutierrez C, Garcia C, Compte T, et al. Cardiovascular effects of the partial or complete correction of anemia with erythropoietin therapy in predialysis patients [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):156‐7. [CENTRAL: CN‐00446594]

Meloni 2003 {published data only}

Meloni C, Tozzo C, Rossi V, Borzi M, Flamini M, Grotta BD, et al. Early anaemia correction with EPO: one year effects on LVH and progression of chronic renal failure (CRF) in predialysis patients (PTS) [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):157. [CENTRAL: CN‐00446732]

Mignon 2001 {published data only}

Mignon F, Andrassy K, Esnault VL, Kuhlmann MK, Sinnassamy P. Epoetin delta corrects and maintains haemoglobin in pre‐end stage renal disease [abstract]. 38th Congress. European Renal Association. European Dialysis and Transplantation Association; 2001 Jun 24‐27; Vienna, Austria. 2001:140. [CENTRAL: CN‐00461317]
Mignon F, Andrassy K, Esnault VL, Kuhlmann MK, Sinnassamy P, European HMR4396 Study Group. Novel human erythropoietin corrects and maintains hemoglobin in pre‐end stage renal disease (ESRD) when administered twice weekly subcutaneously [abstract no: A0384]. Journal of the American Society of Nephrology 2000;11(Sept):71A. [CENTRAL: CN‐00794723]

Muirhead 1992 {published data only}

Muirhead N. Changes in quality of life in chronic renal failure patients treated with recombinant human erythropoiein [abstract]. 9th Asian Colloquium in Nephrology; 1992 May 17‐21; Seoul, Korea. 1992:45‐6. [CENTRAL: CN‐00461371]

N0287023177 {published data only}

Bradley JR. An open label prospective randomised comparative group study to assess the effects of epoeitin alfa therapy in predialysis chronic renal failure patients at an early stage in the development of their anaemia. www.nihr.ac.uk/Profile/Pages/NRRResults.aspx?publication_id=N0287023177 (last accessed 3 July 2014).

Palazzuoli 2007 {published data only}

Palazzuoli A, Silverberg DS, Iovine F, Calabro A, Campagna MS, Gallotta M, et al. Effects of beta‐erythropoietin treatment on left ventricular remodeling, systolic function, and B‐type natriuretic peptide levels in patients with the cardiorenal anemia syndrome. American Heart Journal 2007;154(4):645.e9‐15. [MEDLINE: 17892986]

Pratt 2006 {published data only}

Pratt RD. Epoetin delta for the treatment of anemia in patients with CKD not requiring hemodialysis [abstract no: TH‐PO377]. Journal of the American Society of Nephrology 2006;17(Abstracts):187A. [CENTRAL: CN‐00765050]

Schwartz 1989 {published data only}

Prior JE, Terzian A, Schwartz AB, Kim KE, Mintz GS, Kahn SB. Prolonged RBC survival and hematopoietic response to recombinant human erythropoietin (rHuEPO) in chronic renal failure (CRF) [abstract]. Kidney International 1989;35(1):318. [CENTRAL: CN‐00766056]
Schwartz AB, Mintz GS, Kim KE, Prior JE, Kahn SB. Recombinant human erythropoietin (rHuEPO) increases MAP, TPRI and systolic and diastolic dysfunction with increased impedance to LV ejection due to increased HCT and RBC mass in PTS with CRF [abstract]. Kidney International 1989;35(1):334. [CENTRAL: CN‐00766227]

Singh 1999 {published data only}

Singh NP, Aggarwal L, Singh T, Anuradha S, Kohli R. Anaemia, iron studies and erythropoietin in patients of chronic renal failure. Journal of the Association of Physicians of India 1999;47(3):284‐90. [MEDLINE: 10999121]

Teehan 1990 {published data only}

Teehan P, Benz R, Sigler M, Brown J. Early intervention with recombinant human erythropoietin therapy. Seminars in Nephrology 1990;10(2 Suppl 1):28‐34. [MEDLINE: 2192414]

Yamazaki 1993 {published data only}

Yamazaki C, Watanabe Y, Sakamoto N. Pharmacokinetic study of recombinant human erythropoietin treatment in pre‐dialysis end stage renal disease patients. Nippon Jinzon Gakkai Shi [Japanese Journal of Nephrology] 1993;35(11):1233‐42. [MEDLINE: 8139135]

Zheng 1992 {published data only}

Zheng FL, Bi ZQ, Yang ZP, Li XW, Pu YF, Duan L. Effect of administration of low doses of rHuEPO in predialysis patients [abstract]. 9th Asian Colloquium in Nephrology; 1992 May 17‐21; Seoul, Korea. 1992:175. [CENTRAL: CN‐00462065]

Canadian EPO Study Group 1990

Anonymous. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group. BMJ 1990;300(6724):573‐8. [MEDLINE: 2108751]

Garcia 1985

Garcia DL, Anderson S, Rennke HG, Bremner BM. Anemia lessens and its prevention with recombinant human erythropoietin worsens glomerular injury and hypertension in rats with reduced renal mass. Proceedings of the National Academy of Sciences of the United States of America 1988;85(16):6142‐6. [MEDLINE: 3413082]

Harnett 1995

Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney International 1995;47(3):884‐90. [MEDLINE: 7752588]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [MEDLINE: 12958120]

Higgins 2011

Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Jensen 1994

Jensen JD, Madsen JK, Jensen LW, Pedersen EB. Reduced production, absorption, and elimination of erythropoietin in uremia compared with healthy volunteers. Journal of the American Society of Nephrology 1994;5(2):177‐85. [MEDLINE: 7993997]

Koch 1991

Koch KM, Frei U. Treatment of renal anemia, 1960‐1990. Advances in Nephrology From the Necker Hospital 1991;20:19‐30. [MEDLINE: 2063711]

Levin 1996

Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. American Journal of Kidney Diseases 1996;27(3):347‐54. [MEDLINE: 8604703]

Lin 1985

Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, et al. Cloning and expression of the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America 1985;82(22):7580‐4. [MEDLINE: 3865178]

Lundin 1989

Lundin AP. Quality of life: subjective and objective improvements with recombinant human erythropoietin therapy. Seminars in Nephrology 1989;9(1 Suppl 1):22‐9. [MEDLINE: 2648517]

Muirhead 1994

Muirhead N, Cattran DC, Zaltman J, Jindal K, First MR, Boucher A, et al. Safety and efficacy of recombinant human erythropoietin in correcting the anemia of patients with chronic renal allograft dysfunction. Journal of the American Society of Nephrology 1994;5(5):1216‐22. [MEDLINE: 7873732]

Palmer 2012

Palmer SC, Nand K, Dwi Nur Hidayati L, Munasinghe A, Nelson C, Khafaji MM, et al. Continuous erythropoiesis receptor activator (CERA) for the anaemia of chronic kidney disease. Cochrane Database of Systematic Reviews 2012, Issue 6. [DOI: 10.1002/14651858.CD009904]

Palmer 2014

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Sheingold 1990

Sheingold SH. Cost‐benefit analysis of using recombinant human erythropoietin for the anemia of chronic renal failure. Kidney International ‐ Supplement 1990;3(7):20.

Thompson 1994

Thompson SG. Why sources of heterogeneity in meta‐analysis should be investigated. BMJ 1994;309(6965):1351‐5. [MEDLINE: 7866085]

Ward 1990

Ward HJ. Implications of recombinant erythropoietin therapy for renal transplantation. American Journal of Nephrology 1990;10 Suppl 2:44‐52. [MEDLINE: 2260618]

Winearls 1986

Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;2(8517):1175‐8. [MEDLINE: 2877323]

References to other published versions of this review

Cody 2001

Cody J, Daly C, Campbell M, Donaldson C, Grant A, Khan I, et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre‐dialysis patients. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD003266]

Cody 2005

Cody JD, Daly C, Campbell MK, Khan I, Rabindranath KS, Vale L, et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre‐dialysis patients. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: 10.1002/14651858.CD003266.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Abraham 1990

Methods

  • Study design: parallel RCT with short‐ and long‐term phases

  • Duration of study: 8 to 12 weeks until HCT reached goal of 40% for males and 37% for females

Participants

  • Country: USA

  • Setting: single centre

  • Clinically stable for at least 1 month prior to therapy (BP, physical examination, chemistry profile, electrocardiogram, chest X‐ray, diet and medications)

    • Kidney function: SCr > 3.0 mg/dL

    • Anaemia: HCT < 36%

  • Number: treatment group (4); control group (4)

  • Mean age: 47 years

  • Sex (M/F): treatment group (2/2); control group (3/1)

  • Exclusion criteria: anaemia other than renal anaemia; concomitant therapy with androgen; immunosuppressant or corticosteroid therapy within 2 months; other conditions which might interfere with or complicate EPO therapy including active hepatitis; asthma or severe allergic diathesis; active ischaemic heart disease; SLE; chronic inflammatory diseases; acute rheumatoid arthritis; severe or uncontrolled hypertension (supine diastolic BP > 110 mm Hg); thrombocytopenia (< 100,000/mm³); neutropenia (< 2000/mm3); drug abuse; history of seizures; malignancy; pregnancy

Interventions

Treatment group

  • Type of EPO: erythropoietin alfa

  • Route of administration: IV or SC

  • Dose: 50 to 150 units/kg 3 times/week

Control group

  • Placebo

  • Route of administration: IV or SC

  • Dose: not described

Co‐interventions (both groups)

  • Iron administered: If serum iron < 50 µg/dL or Fe/TIBC < 20% ferrous sulphate

  • Folate administered: daily 1 mg

Duration of study: 8 to 12 weeks until goal HCT of 40% (males) or 37% (females)

Outcomes

  • HCT

  • SCr

  • Number with an increase or introduction of antihypertensive treatment

Notes

  • Formed part of multicentre study (Teehan 1991)

  • Conducted in USA

  • Funded by Ortho Pharmaceuticals

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Unclear, reported to be randomised however method not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Unclear, states "double‐blind placebo‐controlled..."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients completed the first phase of the study

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported

Other bias

High risk

"Financial support and erythropoietin was provided by Ortho Pharmaceutical Corporation, Raritan, N.J., USA"

Akizawa 1993

Methods

  • Study design: unclear

  • Duration of study: 12 weeks

Participants

  • Country: Japan

  • Setting: not reported

  • Participants with CKD not on dialysis

    • Kidney function: SCr 5.7 ± 1.2 mg/dL

    • Anaemia: not reported

  • Number: 107 (did not specify how many were in each group)

  • Age: not reported

  • Sex (M/F): not reported

Interventions

Treatment group

  • Type of EPO: not reported

  • Route of administration: SC

  • Dose: 6000 IU/week for 12 weeks

Control group

  • Placebo

Outcomes

  • GFR

  • HCT

Notes

  • Abstract only

  • Funding: not reported

Brown 1995

Methods

  • Study design: parallel RCT

  • Duration of study: 1 year

Participants

  • Country: USA

  • Setting: single centre

  • Anaemic diabetic predialysis patients

    • Kidney function: SCr 221 to 442 µmol/L

    • Anaemia: HCT < 30%

  • Number: treatment group (8); control group (9)

  • Age: not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not mentioned

Interventions

Treatment group

  • Type of EPO: erythropoietin alfa

  • Route of administration: SC

  • Dose: 50 U/kg 3 times/week

Control group

  • Usual care: not reported

Duration of study: 1 year

Outcomes

  • HCT

  • SCr

Notes

  • Abstract only

  • Funding: not reported

Clyne 1992

Methods

  • Study design: parallel RCT

  • Duration of study: 12 weeks

Participants

  • Country: Sweden

  • Setting: Karolinska Hospital and Danderyd Hospitals

  • CKD patients

    • Kidney function: eGFR < 25 mL/min/1.73 m2

    • Anaemia: HCT ≤ 28%

  • Number: treatment group (12); control group (10)

  • Mean age ± SD (years): treatment group (46 ± 12), control group (53 ± 15)

  • Sex (M/F): treatment group (6/6), control group (5/3)

  • Exclusion criteria: RRT; diabetes; angina or prior acute myocardial infarction; platelet count of > 500 x 109/L; epilepsy; treatment with cytotoxic agents; hormone preparations or immunosuppressants; poorly controlled hypertension; and deficiency of folic acid or vitamin B12

Interventions

Treatment group

  • Type of EPO: Epoetin beta

  • Starting at 300 U/kg/week IV to achieve HCT > 30% for 3 months

Control group

  • No treatment for 3 months

Iron supplementation

  • Oral or IV

Duration of treatment: 12 weeks

Outcomes

  • Number starting RRT during study period

  • Change in QoL

  • Hb

  • GFR

  • Systolic BP

  • Number with an increase or introduction of antihypertensive treatment

Notes

  • Funding: unable to determine

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

"Open randomised parallel‐group study"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

Attrition was 1/12 (8%) in the epoetin beta arm and 2/10 (20%) in the control arm. As this was > 10% overall this was judged to be high risk

Selective reporting (reporting bias)

High risk

Major cardiovascular outcomes were not available

Other bias

Unclear risk

Unable to determine

Eschbach 1989

Methods

  • Study design: parallel RCT, short‐term phase followed by open‐label maintenance phase

  • Duration of study: April 1987 to August 1988

Participants

  • Country: USA

  • Setting: single centre

  • CKD patients

    • Kidney function: SCr 353 to 972 µmol/L

    • Anaemia: HCT < 30%

  • Number: treatment group (11); control group (6)

  • Age range: 24 to 72 years

  • Sex (M/F): 10/7

  • Exclusion criteria: inflammatory disease; immunosuppressive therapy

Interventions

Treatment group

  • Type of EPO: erythropoietin alfa

  • Route of administration: IV and SC

  • Dose: 50, 100 or 150 U/kg 3 times/week

  • Duration of study

    • IV: 8 weeks or until target HCT reached

    • SC: 12 weeks or until target HCT reached

Control group

  • Placebo, IV or SC 3 times/week

Outcomes

  • SCr

  • HCT

Notes

  • Formed part of multicentre study (Teehan 1991)

  • Funding: part funded by Ortho Pharmaceuticals

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Patients and physicians blinded were blinded to the identify of the study medication but not the dose

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients completed the short phase study

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

High risk

Portions of this study were funded by research grants from National Institutes of Health and Ortho Pharmaceutical Corporation.

Ganguli 2003

Methods

  • Study design: parallel 3‐arm RCT

  • Duration of study: 6 months

Participants

  • Country: India

  • Setting: single centre

  • Anaemic non diabetic predialysis patients

    • Kidney function: SCr 3.42 ± 0.27 mg

    • Anaemia: Hb 7.83 ± 24 g/dL

  • Number: treatment group 1 (12); treatment group 2 (12); control group (12)

  • Age range: 18 to 75 years

  • Sex (M/F): treatment group 1 (6/6); treatment group 2 (6/6); control group (6/6)

  • Exclusion criteria: diabetics

Interventions

Treatment group 1

  • Type of EPO: not reported

  • Route of administration: SC

  • Dose: 100 U/kg 2 divided doses a week

Treatment group 2

  • Nandrolone 200 mg IM

Control group

  • Placebo, route and dose not reported

Duration of study: 6 months

Outcomes

  • Anthropometric measurements

  • Haematological parameters

  • Serum albumin

  • SCr

  • Treadmill tests

  • Work capacity

  • QoL

  • Progression of kidney disease

Notes

  • Abstracts only

  • Treatment group 2 not included in the meta‐analyses

  • Study could not be included in the meta‐analyses

  • Funding: not reported

Kim 2006e

Methods

  • Study design: parallel RCT

  • Duration of study: said to continue for 21 months

Participants

  • Country: Korea

  • Setting: multicentre

  • Patients with CKD not on dialysis

    • Kidney function: SCr 1.5 to 4 mg/dL

    • Anaemia: Hb < 10 g/dL

  • Number: treatment group (60); control group (43)

  • Age: not reported (reported no statistical difference between the 2 groups)

  • Sex: not reported (reported no statistical difference between the 2 groups)

  • Exclusion criteria: not reported

Interventions

Treatment group

  • EPO (no dose provided) SC for 3 months of stabilisation to Hb 10 g/L

Control group

  • Placebo SC injections for 3 months

Study said to continue for further 21 months but unclear whether all patients received EPO after 3 months

Outcomes

  • Composite of doubling of SCr

  • Initiation of dialysis

  • Death

Notes

  • Abstract only

  • Funding: not reported

Kleinman 1989

Methods

  • Study design: parallel RCT

  • Duration of study: 12 weeks or until reaching a HCT 38% to 40%

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: stable laboratory parameters; adequate serum folate and B12 levels and iron stores, as reflected by serum iron; total iron binding capacity and ferritin; ensured that anaemia was not caused by a vitamin or elemental iron deficiency; no evidence of chronic gastrointestinal blood loss

    • Kidney function: SCr 265 to 972 µmol/L

    • Anaemia: HCT < 30%

  • Number: treatment group (7); control group (7)

  • Age range: 38 to 73 years

  • Sex M/F: treatment group (5/2); control group (4/3)

  • Exclusion criteria: marked obesity or inanition; active hepatitis or hepatic disease; asthma; severe atopic illness; significant cardiovascular, pulmonary, malignant, or haematologic diseases; severe or uncontrolled hypertensive disease; neurological disease or history of seizure activity; presence of gross haematuria, sickle cell anaemia, untreated ischaemic heart disease of 3 months duration or presence of clinically significant gastrointestinal disease; systemic diseases such as lupus erythematosus, rheumatoid arthritis or other inflammatory diseases or infectious states that might interfere with the effects of EPO; thrombocytopenia or leukopenia; alcohol or drug abuse; acute illness within 7 days of initiation of the screening period; androgen therapy for chronic anaemia corticosteroid and other immunosuppressive medications were discontinued 2 and 1 months respectively before study entry

Interventions

Treatment group

  • Type of EPO: erythropoietin alfa

  • Dose: 100 U/kg 3 times/week

  • Route of administration: SC

Control group

  • Placebo:

  • Route of administration: SC

  • Dose: 3 times/week

Iron administered

  • All received oral iron

Duration of study: 12 weeks or until HCT of 38% or 40%

Outcomes

  • Change in quality of life measures

  • Discontinued due to adverse events

  • Increase or introduction of antihypertensive treatment

  • Need for blood transfusions

Notes

  • Funding: EPO prepared by recombinant DNA technology (Amgen Corporation)

  • "After the 12‐week control period, the seven placebo patients received r‐HuEPO subcutaneously at a dose of 150 U/kg until the target hematocrit of 38% to 40% was reached. The difference in dosages between the two groups was determined by the Ortho Pharmaceutical Corporation before the study"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

1 patient withdrew from EPO group

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

High risk

Ortho Pharmaceutical Corporation was an author on the paper

Kristal 2008

Methods

  • Study design: quasi‐RCT

  • Duration of study: 20 weeks; 2000 to 2001

Participants

  • Country: Israel

  • Setting: unclear

  • Patients with CKD stages 4‐5 not on dialysis or EPO

    • Kidney function: not reported

    • Anaemia: Hb 8.1 to 11 g/dL

  • Number: treatment group (20); control group (20)

  • Mean age ± SEM (years): treatment group (70.2 ± 2.0); control group (67.2 ± 2.7)

  • Sex (M/F): treatment group (4/16); control group (6/14)

  • Exclusion criteria: not reported

Interventions

Treatment group

  • Type of EPO: Eprex

  • Dose: 6000 IU/week

  • Route of administration: SC

Control group

  • No treatment

All patients received oral maintenance iron supplementation, calcium bicarbonate, statins, beta‐blockers, and calcium channel blockers

Outcomes

  • SCr

  • Calculated GFR

  • Hb

Notes

  • Primary outcomes of study related to non‐erythropoietic actions of EPO

  • Funding: "This work was partially supported by a grant from by the R.W. Johnson Pharmaceutical Research Institute, a division of Ortho‐McNeil Pharmaceutical, Inc."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

High risk

Patients allocated in order according to visit to clinic (information from authors)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding; open label

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Relevant outcomes were laboratory based and unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

High risk

12/40 (30%) did not complete study (3/20 in treatment group and 9/20 in control group)

Selective reporting (reporting bias)

High risk

No report of adverse effects

Other bias

Unclear risk

Unable to determine

Kuriyama 1997

Methods

  • Study design: parallel RCT

  • Duration of study: commenced 1 January 1993

Participants

  • Country: Japan

  • Setting: single centre

  • Predialysis patients aged 30 and 75 years

    • Kidney function: SCr 2 to 4 mg/dL

    • Anaemia: HCT < 30%

  • Number: treatment group (43; control group (31)

  • Mean age ± SD (years): treatment group (63.8 ± 10.6); control group (59.2 ± 13.4)

  • Sex (males): treatment group (55%); control group (52%)

  • Exclusion criteria: iron deficiency anaemia; transfusion dependency; presence of any other systemic disease; any inflammatory condition or infection that might interfere with the effect of EPO

Interventions

Treatment group

  • Type of EPO: not reported

  • Dose: 6,000 IU once a week varied to achieve target HCT of 33% to 35%

  • Route of administration: IV

Control group

  • No treatment

Iron: at the investigators discretion
Duration of study: 36 weeks

Outcomes

  • Patients whose creatinine doubled regarded as having reached kidney death

  • Inability to attend regularly and death from non‐kidney disease

  • Number commencing dialysis

  • HCT

Notes

  • Funding: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Control group received no treatment

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients accounted for

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

Unclear risk

Unable to determine

Lim 1989

Methods

  • Study design: 4‐arm parallel RCT

  • Duration of study: 8 weeks

Participants

  • Country: USA

  • Setting: single centre

  • Adults with renal insufficiency

    • Kidney function: SCr 548.08 ± 70.72 µmol/L

    • Anaemia: HCT 27% ± 1%

  • Number: treatment group (11); control group (3)

  • Age range: 30 to 70 years

  • Sex M/F: 10/4

  • Exclusion criteria: active lupus; malignancy; haemolysis; bleeding; clinically unstable; taking steroid or immunosuppressive medication

Interventions

Treatment group

  • Type of EPO: not reported

  • Dose: 50, 100 and 150 U/kg 3 times/week

  • Route of administration: IV

Control group

  • Placebo

  • Route of administration: IV

Iron administered: ferrous sulphate 300 mg orally 3 x day
Folate administered: folic acid 1 mg orally daily
Duration of study: 8 weeks

Outcomes

  • Change in quality of life measures

  • Number discontinued due to adverse events

  • Number with an increase or introduction of antihypertensive treatment

  • Number who need blood transfusions

  • Number experiencing seizures

  • Exercise tolerance

  • HCT levels

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Third party

Allocation concealment (selection bias)

Low risk

Adequate, third party

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Unable to determine

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

Unclear risk

Unable to determine

Roth 1994

Methods

  • Study design: parallel RCT

  • duration of study: 48 weeks

Participants

  • Country: USA

  • Setting: 11 centres

  • CKD patients aged 18 to 75 years; mean arterial pressure controllable below 114 mm Hg; not currently receiving HD treatment

    • Kidney function: SCr 265.2 to 707.2 µmol/L

    • Anaemia: HCT < 30%

  • Number: treatment group (43); control group (40)

  • Mean age ± SE (years): treatment group (56.5 ± 11.4); control group (58.4 ± 13.2)

  • Sex (females): treatment group (65%); control group (70%)

  • Exclusion criteria: proteinuria > 5g/d; iron deficiency anaemia; transfusion dependency; presence of any other systemic disease, inflammatory condition, infection that might interfere with effects of EPO

Interventions

Treatment group

  • Type of EPO: not reported

  • Dose: 50 U/kg 3 times/week which could be increased 75 U/kg/week on a monthly basis to a maximum of 450 U/kg/week

  • Route of administration: SC; could self‐administer after 1st month

Control group

  • No treatment

Iron administered: investigators discretion
Folate administered: no
Duration of study: 48 weeks

Outcomes

  • Number of starting RRT during study period

  • Number discontinued due to adverse events

  • GFR

  • Decrease in GFR

  • Increase in SCr level

  • Number with an increase or introduction of antihypertensive treatment

  • Number who need blood transfusions

  • Mortality

Notes

  • Funding: "Supported by a grant from the R. W. Johnson Pharmaceutical Research Institute and Ortho Biotech Inc. Raritan. NJ."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open label

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Nor reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

23/43 in the EPO group and 25/40 in the control group did not complete the study

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

High risk

Funded by Ortho Biotech

Stone 1988

Methods

  • Study design: parallel 4‐arm RCT

  • Duration of study: 8 weeks

Participants

  • Country: USA

  • Setting: multicentre

  • Patients with chronic renal insufficiency

    • Kidney function: CrCl 0.17 to 0.51 mL/s (10 to 30 mL/min)

    • Anaemia: PCV < 41% males; 35% females

  • Number: treatment group (9); control group (3)

  • Mean age (range): 62 years (45 to 73 years)

  • Sex M/F: 11/1

  • Exclusion criteria: severe allergic disorders; asthma; active hepatitis; history of seizures; malignancy; uncontrolled hypertension; ischaemic heart disease; neutropenia; iron deficiency; haemolytic anaemia; thrombocytopenia

Interventions

Treatment group

  • Type of EPO: erythropoietin alfa

  • Dose: 50, 100 or 150 U/kg 3 times/week

  • Route of administration: IV

  • Administered by: 1st and last dose in hospital all others in outpatient clinic

Control group

  • Placebo 3 times/week

  • Route of administration: IV

  • Administered by: 1st and last dose in hospital all others in outpatient clinic

Iron administered: ferrous sulphate 300 mg 3 times/day

Folate administered: 1 mg daily

Duration of study: 8 weeks

Outcomes

  • Number progressing to dialysis

  • Number with increase or introduction of antihypertensives

  • Mortality

Notes

  • Formed part of multicentre study (Teehan 1991)

  • Funded in part by a grant from Ortho Pharmaceutical Corporation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind, placebo controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Unable to determine

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

High risk

Funded by Ortho Pharmaceutical

Teehan 1989

Methods

  • Study duration: parallel RCT

  • Study duration: 3 months

Participants

  • Country: USA

  • Setting: single centre

  • Predialysis CKD patients

    • Kidney function: mean SCr 5.1 ± 2.4 mg/dL

    • Anaemia: mean HCT 25.2% ± 3.5%

  • Number: treatment group (6); control group (6)

  • Age: not reported

  • Sex M/F: 6/6

  • Exclusion criteria: patients with gastrointestinal bleeding; acute or chronic infection; sickle‐cell anaemia; collagen vascular disease; known seizure disorder; drug or alcohol abuse; recent myocardial infarction; pregnancy; deficiencies of iron folic acid, or vitamin B12

Interventions

Treatment group

  • Type of EPO: not reported

  • Dose: 100 U/kg 3 times/week

  • Route of administration: SC

Control group

  • Placebo 3 times/week SC

Outcomes

  • Haematology

Notes

  • It was assumed that this study included a different set of patients from the multicentre study (Teehan 1991) since the methods were different i.e. different dosing regimen, different route of administration, different outcome measures and different study duration

  • Funding: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported

Selective reporting (reporting bias)

High risk

Data for cardiovascular outcomes not available

Other bias

Unclear risk

Unable to determine

Teehan 1991

Methods

  • Study design: parallel 4‐arm study

  • Duration of study: 8 weeks

Participants

  • Country: USA

  • Setting: multicentre (15 centres)

  • Anaemic predialysis patients

    • Kidney function: SCr 260 to 880 µmol/L

    • Anaemia: HCT < 38% male; < 32% women

  • Number: treatment group (88); control group (29)

  • Mean age (range): 57.1 years (24 to 79 years)

  • Sex M/F: 71/46

  • Exclusion criteria: significant clinical conditions affecting the hepatic; cardiovascular hematologic (other than anaemia); neurologic; or pulmonary systems

Interventions

Treatment group

  • Type of EPO: not reported

  • Dose: 50, 100 or 150 u/kg 3 times/week

  • Route of administration: IV

Control group

  • Placebo, 3 times/week IV

Folate administered: yes
Duration of study: 8 weeks or until HCT reached 40% for men or 37% for women

Outcomes

  • Number discontinued due to adverse events

  • Number with an increase or introduction of antihypertensive treatment

  • Number experiencing seizures

  • HCT

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

106/117 completed the study

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

High risk

Part funded by Ortho Pharmaceuticals

Teplan 2001b

Methods

  • Study design: parallel 3‐arm RCT

  • Duration of study: 3 years

Participants

  • Country: Czech Republic

  • Setting: single centre

  • Predialysis CKD patients with good compliance to diet

    • Kidney function: 22 to 36 mL/min/1.73m2

    • Anaemia: Hb < 11.5 g/dL, HCT < 32%

  • Number: treatment group 1 (35); treatment group 2 (38), control group (32)

  • Age range: 26 to 78 years

  • Sex M/F: 50/55

  • Exclusion criteria: not reported

Interventions

Treatment group 1

  • EPO + low protein diet + keto acids

  • Type of EPO: not reported

  • Dose: 40 U/kg/week

  • Route of administration: unclear

Treatment group 2

  • EPO + low protein diet

  • Type of EPO: not reported

  • Dose: 40 U/kg/week

  • Route of administration: unclear

Control group

  • Low protein diet

Duration of study: 3 years

Outcomes

  • GFR (CrCl and inulin clearance)

  • Serum branched chain amino acids

  • Albumin

  • Transferrin

  • BMI

  • HDL cholesterol

  • Proteinuria

  • Serum triglycerides

  • Serum fractional leucine excretion

Notes

  • Abstract only

  • Funding: not reported

Teplan 2003

Methods

  • Study design: parallel 3‐arm RCT

  • Duration of study: 36 months

Participants

  • Country: Czech Republic

  • Setting: multicentre study

  • Patients with good compliance to diet preceding entry to study

    • Kidney function: CrCl (29.4 ± 8.2 mL/min); SCr (2.79 ± 0.97 mg/dL)

    • Anaemia: Hb < 10.5 g/dL

  • Number: treatment group 1 (63); treatment group 2 (61); control group (62)

  • Mean age ± SD: 52 ± 8 years

  • Sex M/F: treatment group 1 (31/32); treatment group 2 (29/32); control group (30/32)

  • Exclusion criteria: diabetic kidney disease; polycystic kidney disease

Interventions

Treatment group 1

  • EPO + low protein diet + keto acids

  • EPO: epoetin alfa and epoetin beta

    • Dose: 40 U/kg twice a week

    • Route of administration: SC

  • Keto acids: 100 mg/kg/d

Treatment group 2

  • EPO + low protein diet

Control group

  • Low protein diet: 0.6 g protein/kg/d

Duration of study: 36 months

Outcomes

  • CrCl

  • Inulin clearance

  • SCr

  • Serum urea

  • Serum leucine

  • Serum albumin

  • Proteinuria

  • Serum cholesterol

  • Serum LDL cholesterol

  • Serum triglyceride

  • Serum HDL cholesterol

  • Hb

  • BP

Notes

  • Author confirmed sealed envelopes were used for allocation concealment

  • Funding: "Supported by grant no. 305/01/0578 from the Grant Agency of the Czech Republic."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Low risk

Adequate; sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open label

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients accounted for

Selective reporting (reporting bias)

Unclear risk

Only biochemical parameters reported

Other bias

Unclear risk

Unable to determine

Wang 2004b

Methods

  • Study design: parallel RCT

  • Duration of study: 48 weeks

Participants

  • Country: Hong Kong

  • Setting: single centre

  • Patients with CKD not on dialysis

    • Kidney function: SCr 150 to 750 µmol/L

    • Anaemia: Hb < 11 g/dL

  • Number: treatment group (32); control group (34)

  • Age: not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Treatment group

  • EPO 4000 IU weekly SC.

  • Dose titrated to achieve and maintain Hb 12 to 14 g/dL

Control group

  • No treatment

Outcomes

  • GFR

  • Hb

Notes

  • Abstract only

  • Other outcomes were surrogate markers for vascular function

  • Funding: not reported

Watson 1990

Methods

  • Study design: parallel RCT

  • Duration of study: 12 weeks

Participants

  • Country: USA

  • Setting: single centre

  • Patients with pre‐existing CKD

    • Kidney function: not reported

    • Anaemia: not reported

  • Number: treatment group (5); control group (6)

  • Age range: 43 to 79 years

  • Sex M/F: 6/5

  • Exclusion criteria:

Interventions

Treatment group

  • Type of EPO: not reported

  • Route of administration: SC

  • Dose: 100 U/kg 3 times/week

Control group

  • Placebo

Duration of study: 12 weeks or until target HCT of 38% is achieved

Outcomes

  • HCT

  • Number discontinued due to adverse events

  • GFR

  • SCr

  • Number experiencing seizures

Notes

  • Funding: "supported in part by Orth Pharmaceuticals Inc. and by grants DK 32008 and CRC 5‐M01RR00722 from the National Institutes of Health"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Performed by a third party

Allocation concealment (selection bias)

Low risk

Performed by a third party

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Stated double blind; placebo used

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients accounted for

Selective reporting (reporting bias)

Unclear risk

Unable to determine

Other bias

High risk

Funded by Ortho Pharmaceuticals

BP ‐ blood pressure; CKD ‐ chronic kidney disease; CrCl ‐ creatinine clearance; EPO ‐ erythropoietin; GFR ‐ glomerular filtration rate; Hb ‐ haemoglobin; HCT ‐ haematocrit; HDL ‐ high‐density lipoprotein; IV ‐ intravenous; LDL ‐ low‐density lipoprotein; M/F ‐ male/female; PCV ‐ packed cell volume; QoL ‐ quality of life; RCT ‐ randomised control trial; RRT ‐ renal replacement therapy; SC ‐ subcutaneous; SCr ‐ serum creatinine; SD ‐ standard deviation; SE ‐ standard error

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Brown 1988

All patients received EPO

CREATE Study 2001

Comparing the same ESA derivative in different treatment arms

EPOCARES Study 2010

Ineligible population

Frenken 1989

All patients received EPO

Frenken 1992

All patients received EPO

Furukawa 1992

All patients received EPO

Jabs 1994

Not randomised

Koene 1990

All patients received EPO

Macdougall 2007

Compares early with late commencement of EPO

Marcas 2003

All patients received EPO

Meloni 2003

Unclear how patients allocated to groups. Written to authors for clarification

Mignon 2001

All patients received EPO

Muirhead 1992

Haemodialysis patients

N0287023177

All patients received EPO

Palazzuoli 2007

Ineligible population. Cardiac failure patients

Pratt 2006

Compares EPO delta with EPO alpha

Schwartz 1989

Data only from EPO treated patients

Singh 1999

Randomised study. Not all participants were predialysis some had commenced dialysis

Teehan 1990

Unclear if randomised. Wrote to authors all patients received EPO

Yamazaki 1993

All patients received EPO

Zheng 1992

All patients received EPO

EPO ‐ erythropoietin

Data and analyses

Open in table viewer
Comparison 1. rHuEPO versus placebo or no rHuEPO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number starting RRT Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 1 Number starting RRT.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 1 Number starting RRT.

1.1 Starting RRT during the study period

5

207

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.43, 1.14]

1.2 Starting RRT in the follow‐up to the study

1

8

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.50, 17.95]

2 GFR Show forest plot

7

283

Mean Difference (IV, Random, 95% CI)

‐2.11 [‐3.08, ‐1.15]

Analysis 1.2

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 2 GFR.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 2 GFR.

3 Reduction in GFR Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 1.3

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 3 Reduction in GFR.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 3 Reduction in GFR.

4 Serum creatinine Show forest plot

8

327

Mean Difference (IV, Random, 95% CI)

27.86 [‐32.04, 87.76]

Analysis 1.4

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 4 Serum creatinine.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 4 Serum creatinine.

5 Increase in serum creatinine Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 1.5

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 5 Increase in serum creatinine.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 5 Increase in serum creatinine.

6 Haemoglobin Show forest plot

4

237

Mean Difference (IV, Random, 95% CI)

‐1.90 [‐2.34, ‐1.47]

Analysis 1.6

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 6 Haemoglobin.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 6 Haemoglobin.

7 Haematocrit Show forest plot

7

145

Mean Difference (IV, Random, 95% CI)

‐9.85 [‐11.34, ‐8.35]

Analysis 1.7

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 7 Haematocrit.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 7 Haematocrit.

8 Number of patients transfused Show forest plot

3

111

Risk Ratio (M‐H, Random, 95% CI)

0.32 [0.12, 0.83]

Analysis 1.8

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 8 Number of patients transfused.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 8 Number of patients transfused.

9 Quality of life measures Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 1.9

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 9 Quality of life measures.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 9 Quality of life measures.

10 Change in exercise capacity Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 1.10

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 10 Change in exercise capacity.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 10 Change in exercise capacity.

11 Systolic blood pressure Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 1.11

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 11 Systolic blood pressure.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 11 Systolic blood pressure.

12 Diastolic blood pressure Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 1.12

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 12 Diastolic blood pressure.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 12 Diastolic blood pressure.

13 Number with an increase or introduction of antihypertensive treatment Show forest plot

4

232

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.76, 2.11]

Analysis 1.13

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 13 Number with an increase or introduction of antihypertensive treatment.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 13 Number with an increase or introduction of antihypertensive treatment.

14 Number discontinued due to adverse events Show forest plot

4

223

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.28, 2.59]

Analysis 1.14

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 14 Number discontinued due to adverse events.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 14 Number discontinued due to adverse events.

15 Seizures Show forest plot

3

140

Risk Ratio (M‐H, Random, 95% CI)

0.22 [0.02, 1.94]

Analysis 1.15

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 15 Seizures.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 15 Seizures.

16 Mortality Show forest plot

4

182

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.13, 2.88]

Analysis 1.16

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 16 Mortality.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 16 Mortality.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
 The empty rows relate to abstract‐only publications ‐ risk of bias could not be assessed
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
The empty rows relate to abstract‐only publications ‐ risk of bias could not be assessed

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 1 Number starting RRT.
Figures and Tables -
Analysis 1.1

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 1 Number starting RRT.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 2 GFR.
Figures and Tables -
Analysis 1.2

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 2 GFR.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 3 Reduction in GFR.
Figures and Tables -
Analysis 1.3

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 3 Reduction in GFR.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 4 Serum creatinine.
Figures and Tables -
Analysis 1.4

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 4 Serum creatinine.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 5 Increase in serum creatinine.
Figures and Tables -
Analysis 1.5

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 5 Increase in serum creatinine.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 6 Haemoglobin.
Figures and Tables -
Analysis 1.6

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 6 Haemoglobin.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 7 Haematocrit.
Figures and Tables -
Analysis 1.7

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 7 Haematocrit.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 8 Number of patients transfused.
Figures and Tables -
Analysis 1.8

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 8 Number of patients transfused.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 9 Quality of life measures.
Figures and Tables -
Analysis 1.9

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 9 Quality of life measures.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 10 Change in exercise capacity.
Figures and Tables -
Analysis 1.10

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 10 Change in exercise capacity.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 11 Systolic blood pressure.
Figures and Tables -
Analysis 1.11

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 11 Systolic blood pressure.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 12 Diastolic blood pressure.
Figures and Tables -
Analysis 1.12

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 12 Diastolic blood pressure.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 13 Number with an increase or introduction of antihypertensive treatment.
Figures and Tables -
Analysis 1.13

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 13 Number with an increase or introduction of antihypertensive treatment.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 14 Number discontinued due to adverse events.
Figures and Tables -
Analysis 1.14

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 14 Number discontinued due to adverse events.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 15 Seizures.
Figures and Tables -
Analysis 1.15

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 15 Seizures.

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 16 Mortality.
Figures and Tables -
Analysis 1.16

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 16 Mortality.

Comparison 1. rHuEPO versus placebo or no rHuEPO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number starting RRT Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Starting RRT during the study period

5

207

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.43, 1.14]

1.2 Starting RRT in the follow‐up to the study

1

8

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.50, 17.95]

2 GFR Show forest plot

7

283

Mean Difference (IV, Random, 95% CI)

‐2.11 [‐3.08, ‐1.15]

3 Reduction in GFR Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

4 Serum creatinine Show forest plot

8

327

Mean Difference (IV, Random, 95% CI)

27.86 [‐32.04, 87.76]

5 Increase in serum creatinine Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

6 Haemoglobin Show forest plot

4

237

Mean Difference (IV, Random, 95% CI)

‐1.90 [‐2.34, ‐1.47]

7 Haematocrit Show forest plot

7

145

Mean Difference (IV, Random, 95% CI)

‐9.85 [‐11.34, ‐8.35]

8 Number of patients transfused Show forest plot

3

111

Risk Ratio (M‐H, Random, 95% CI)

0.32 [0.12, 0.83]

9 Quality of life measures Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

10 Change in exercise capacity Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

11 Systolic blood pressure Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

12 Diastolic blood pressure Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

13 Number with an increase or introduction of antihypertensive treatment Show forest plot

4

232

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.76, 2.11]

14 Number discontinued due to adverse events Show forest plot

4

223

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.28, 2.59]

15 Seizures Show forest plot

3

140

Risk Ratio (M‐H, Random, 95% CI)

0.22 [0.02, 1.94]

16 Mortality Show forest plot

4

182

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.13, 2.88]

Figures and Tables -
Comparison 1. rHuEPO versus placebo or no rHuEPO