The impact of iron supplementation for treating anemia in patients with chronic kidney disease: Results from pairwise and network meta-analyses of randomized controlled trials

pha maceu icals A icle The Impac o I on Supplemen a ion o T ea ing Anemia in Pa ien s wi h Ch onic Kidney Disease: Resul s om Pai wise and Ne wo k Me a-Analyses o Randomized Con olled T ials Ma cel Adle 1,2, F ancisco He e a-Gómez 2,3,* , Débo a Ma ín-Ga cía4, Ma ie Ga id 2,5, F. Ja ie Ál a ez 2,6 and Ca los Ochoa-Sang ado 7 1Cen e o Medical Oncology & Hema ology, Hospi al Thun, 3600 Thun, Swi ze land; [email p o ec ed] 2Pha macological Big Da a Labo a o y, Uni e si y o Valladolid, 47005 Valladolid, Spain; [email p o ec ed] (M.G.); [email p o ec ed] (F.J.Á.) 3Neph ology, Complejo Asis encial de Zamo a, 49022 Zamo a, Spain 4Neph ology, Uni e si y Clinical Hospi al o Valladolid, 47005 Valladolid, Spain; [email p o ec ed] 5 Ana omy, Facul y o Medicine Jacques Lis anc, Jean Monne Uni e si y, 42270 Sain -P ies en Ja ez, F ance 6E hics Commi ee o D ug Resea ch - Eas Valladolid, Uni e si y Clinical Hospi al o Valladolid, 47005 Valladolid, Spain 7Clinical Epidemiology Resea ch Suppo O ice, Complejo Asis encial de Zamo a, 49022 Zamo a, Spain; [email p o ec ed] *Co espondence: he [email p o ec ed] Recei ed: 16 Ap il 2020; Accep ed: 28 Ap il 2020; Published: 30 Ap il 2020   Abs ac : A e ela i e e y h opoie in de iciency, i on de iciency is he second mos impo an con ibu ing ac o o anemia in ch onic kidney disease (CKD) pa ien s. I on supplemen a ion is a c ucial pa o he ea men o anemia in CKD pa ien s, and in a enous (IV) i on supplemen a ion is conside ed o be supe io o pe os (PO) i on supplemen a ion. The di e ences be ween he a ailable o mula ions a e poo ly cha ac e ized. This epo p esen s esul s om pai wise and ne wo k me a-analyses ca ied ou a e a comp ehensi e sea ch in sou ces o published and unpublished s udies, acco ding o he P e e ed Repo ing I ems o Sys ema ic e iews and Me a-Analyses (PRISMA) ecommenda ions (In e na ional p ospec i e egis e o sys ema ic e iews PROSPERO e e ence ID: CRD42020148155). Me a-analy ic calcula ions we e pe o med o he ou come o non- esponse o i on supplemen a ion (i.e., hemoglobin (Hgb) inc ease o <0.5–1.0 g/dL, o ini ia ion/in ensi ica ion o e y h opoiesis-s imula ing agen (ESA) he apy, o inc ease/change o i on supplemen , o equi emen s o blood ans usion). A o al o 34 andomized con olled ials (RCT) we e iden i ied, p o iding nume ical da a o analyses co e ing 93.7% (n =10.097) o he o al s udy popula ion. A he ne wo k le el, i on supplemen a ion seems o ha e a mo e p o ec i e e ec agains he ou come o non- esponse be o e he s a o dialysis han once dialysis is ini ia ed, and some p epa a ions seem o be mo e po en (e.g., e umoxy ol, e ic ca boxymal ose), compa ed o he es o i on supplemen s assessed (su ace unde he cumula i e anking a ea (SUCRA) >0.8). This s udy p o ides pa ame e s o adequa ely ollowing-up pa ien s equi ing i on supplemen a ion, by p esen ing he mos pe o ming p epa a ions, and, indi ec ly, by making i possible o iden i y good esponde s among all pa ien s ea ed wi h hese medicines. Keywo ds: anemia; i on-de iciency; i on compounds; Kidney Diseases Pha maceu icals 2020,13, 85; doi:10.3390/ph13050085 www.mdpi.com/jou nal/pha maceu icals Pha maceu icals 2020,13, 85 2 o 10 1. In oduc ion A e ela i e e y h opoie in de iciency, i on de iciency is he second mos common con ibu ing ac o o anemia in ch onic kidney disease (CKD) pa ien s [ 1 , 2 ]. Anemia may be conside ed a su oga e ma ke o CKD se e i y, and i s ea men may slow down he p og ession o concomi an hea disease and ca dio ascula disease, as well as he e olu ion o CKD owa ds end-s age kidney disease (ESKD) [3]. In a enous (IV) p epa a ions a e he p e e ed galenic o mula ion o i on supplemen a ion bo h be o e and once dialysis is ini ia ed [ 4 ]. Howe e , he e ec s and bene i s o di e en IV i on supplemen s compa ed o pe os (PO) i on supplemen s a e s ill poo ly cha ac e ized in he di e en s ages o CKD: an accu a e desc ip ion o he impac o di e en i on supplemen a ion o mula ions may imp o e physicians’ decision-making p ocess and p omo e an indi idualized ea men app oach o i on-de iciency anemia (IDA) in CKD pa ien s. Ou s udy aim was o assess ea men esponse o di e en comme cially a ailable i on supplemen s in CKD pa ien s, which was de ined by he inc ease in he hemoglobin (Hgb) le el and/o he need o e y h opoiesis-s imula ing agen (ESA) he apy and o he ea men s o anemia in CKD pa ien s. 2. Resul s The s anda dized lowcha p oduced by he P e e ed Repo ing I ems o Sys ema ic e iews and Me a-Analyses (PRISMA) g oup [ 5 ] is p esen ed in Figu e 1, showing he s udy selec ion p ocess ha led o he inclusion o 34 andomized con olled ials (RCT). All s udies in es iga ing i on supplemen a ion in pa ien s wi h CKD we e sc eened o eligibili y. Non- ele an a icles (e.g., non- esea ch s udies, obse a ional s udies), as well as s udies wi h di e en in es iga ed ou comes, we e excluded. No unpublished s udies we e ound (i.e., mee ing abs ac s, PhD and Mas e Theses, and indus y epo s did no p o ide o he s udies di e en han ha published). Howe e , in some cases mo e han one published a icle/unpublished epo p esen ed he esul s om one s udy, o which ex ension ollow-up s udies/pos -hoc analyses we e iden i ied o h ee s udies: e umoxy ol au ho iza ion s udies [ 6 – 10 ], Dialysis pa ien s’ Response o IV i on wi h Ele a ed e i in (DRIVE) and DRIVE II s udies [ 11 , 12 ], and King’s College Hospi al (KCH)/Royal Adelaide Hospi al (RAH) s udies [ 13 – 15 ]. S udy pa icipan s de ails and he cha ac e is ics o he eligible s udies, as well as de ails o he in e en ions, compa a o s and all ou comes e alua ed in he included ials, as emana e om ou sys ema ic na a i e syn hesis a e a ailable o eade s online (Table S1). Ten ou o he inal 34 included ials did no p o ide nume ical da a o ou planned me a-analy ic assessmen s. Howe e , ma hema ical indings p esen ed he e co e ed 93.7% (n =10.097) o he o al s udy popula ion. Impo an ly, he calcula ion o pooled e ec es ima es o common e icacy pa ame e s (e.g., Hgb and se um ans e in and e i in le els) was no possible, e en i six ou o he analyzable 24 ials pe o med a s a i ied andomiza ion o s udy pa icipan s on hese pa ame e s and o he e icacy and non-e icacy a iables (e.g., ESA he apy and ans usion equi emen s, s udy pa icipan s cha ac e is ics) [ 11 , 12 , 16 – 20 ]. The he e ogenous de ini ion o such a iables was he main cause impeding his analysis. All RCTs in es iga ed we e o mode a e o high quali y (Table S2). Figu e 2shows pai wise me a-analysis o 19 ials, compa ing exclusi ely IV and PO i on supplemen s o he combined ou come o non- esponse (i.e., Hgb inc ease o <0.5–1.0 g/dL, o ini ia ion/in ensi ica ion o ESA he apy, o inc ease/change o i on supplemen , o equi emen s o blood ans usion). Figu e 3shows he Bayesian ne wo k diag ams buil wi h all 24 ials, compa ing di e en IV p epa a ions o PO i on supplemen s. O e all, mo e p epa a ions appea o ha e a p o ec i e e ec agains he combined ou come o non- esponse be o e he s a o dialysis han once dialysis is ini ia ed. Indeed, as depic ed in Figu e 4, 400 mg o mo e o i on suc ose pe mon h (odds a io (OR), 95% c edible in e al (C I); 0.46, 0.30 o 0.68), 100 o 300 mg o i on suc ose pe mon h (0.48, 0.31 o 0.77), 1020 mg o e umoxy ol pe mon h (0.28, 0.16 o 0.47), and 750 o 1500 mg o e ic ca boxymal ose pe mon h (0.36, 0.24 o Pha maceu icals 2020,13, 85 3 o 10 0.53) we e he mos e icien o mula ions among CKD pa ien s in o he Kidney Disease—Imp o ing Global Ou comes (KDIGO) glome ula il a ion a e (GFR) ca ego ies G3A o G5, compa ed o PO i on supplemen s and no i on adminis a ion. Con a ily, only 400 mg o mo e o i on suc ose pe mon h (0.13, 0.02 o 0.50) and 400 mg o mo e o i on dex an pe mon h (0.08, 0.01 o 0.64) we e e icacious among dialysis pa ien s. A he pai wise le el, he e ogenei y was pa icula ly e iden ( I2>50% ). Mo eo e , he asymme y o unnel plo s in ol ing es ima es on bo h pa ien s in he KDIGO GFR ca ego ies G3A o G5 and dialysis pa ien s was impo an (Egge ’s es ( )/deg ees o eedom (d )/p; −2.3591, 17, 0.0305). Pha maceu icals 2020, 13, x FOR PEER REVIEW 3 o 11 compa ed o PO i on supplemen s and no i on adminis a ion. Con a ily, only 400 mg o mo e o i on suc ose pe mon h (0.13, 0.02 o 0.50) and 400 mg o mo e o i on dex an pe mon h (0.08, 0.01 o 0.64) we e e icacious among dialysis pa ien s. A he pai wise le el, he e ogenei y was pa icula ly e iden (I² > 50%). Mo eo e , he asymme y o unnel plo s in ol ing es ima es on bo h pa ien s in he KDIGO GFR ca ego ies G3A o G5 and dialysis pa ien s was impo an (Egge ’s es ( )/deg ees o eedom (d )/p; −2.3591, 17, 0.0305). Figu e 1. PRISMA lowcha s p esen ing ou sys ema ic e iew selec ion p ocess o e ie ing i on supplemen a ion e idence on clinical ials. PRISMA, P e e ed Repo ing I ems o Sys ema ic Re iews and Me a-Analyses. Figu e 1. PRISMA lowcha s p esen ing ou sys ema ic e iew selec ion p ocess o e ie ing i on supplemen a ion e idence on clinical ials. PRISMA, P e e ed Repo ing I ems o Sys ema ic Re iews and Me a-Analyses. Su p isingly, on he basis o he alue o he su ace unde he cumula i e anking a ea (SUCRA), be o e s a ing dialysis, e umoxy ol (>0.9) and e ic ca boxymal ose (0.808), espec i ely, we e ma kedly di e en han i on suc ose p epa a ions (<0.6) and he o he i on supplemen s assessed (Table 1). In he g oup o ch onic dialysis pa ien s, such a di e ence be ween i on supplemen s was no pe cei ed. The model chosen o calcula ing SUCRA alues shows con e gence, bu a deg ee o inconsis ency (Figu e S1). Pha maceu icals 2020,13, 85 4 o 10 Pha maceu icals 2020, 13, x FOR PEER REVIEW 4 o 11 Figu e 2. Fo es and unnel plo s showing e ec es ima es o IV e sus PO i on supplemen s in he wo subg oups con o med. CI, con idence in e al; IV, in a enous; M-H, Man el–Haenszel es ; PBO, placebo; PO, pe os; SE, s anda d e o . Figu e 2. Fo es and unnel plo s showing e ec es ima es o IV e sus PO i on supplemen s in he wo subg oups con o med. CI, con idence in e al; IV, in a enous; M-H, Man el–Haenszel es ; PBO, placebo; PO, pe os; SE, s anda d e o . Pha maceu icals 2020, 13, x FOR PEER REVIEW 5 o 11 (a) (b) Figu e 3. Bayesian ne wo k diag ams p esen ing he densi y in he compa isons ( hickness o lines acco ding o he numbe o RCTs in each compa ison) and he compe ing i on supplemen s (node size acco ding o he numbe o pa icipan s unde going in e en ions) o he subg oups o (a) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and; (b) dialysis pa ien s. GFR, Glome ula il a ion a e; KDIGO, Kidney Disease—Imp o ing Global Ou comes; RCT, andomized con olled ial. (a) (b) Figu e 4. League ables showing ORs and 95% C Is co esponding o he assessed IV i on supplemen s agains he compa a o s in he subg oups o (a) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and; (b) dialysis pa ien s. C I, c edible in e als; OR, odds a io. Figu e 3. Bayesian ne wo k diag ams p esen ing he densi y in he compa isons ( hickness o lines acco ding o he numbe o RCTs in each compa ison) and he compe ing i on supplemen s (node size acco ding o he numbe o pa icipan s unde going in e en ions) o he subg oups o ( a ) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and; ( b ) dialysis pa ien s. GFR, Glome ula il a ion a e; KDIGO, Kidney Disease—Imp o ing Global Ou comes; RCT, andomized con olled ial. Pha maceu icals 2020,13, 85 5 o 10 Pha maceu icals 2020, 13, x FOR PEER REVIEW 5 o 11 (a) (b) Figu e 3. Bayesian ne wo k diag ams p esen ing he densi y in he compa isons ( hickness o lines acco ding o he numbe o RCTs in each compa ison) and he compe ing i on supplemen s (node size acco ding o he numbe o pa icipan s unde going in e en ions) o he subg oups o (a) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and; (b) dialysis pa ien s. GFR, Glome ula il a ion a e; KDIGO, Kidney Disease—Imp o ing Global Ou comes; RCT, andomized con olled ial. (a) (b) Figu e 4. League ables showing ORs and 95% C Is co esponding o he assessed IV i on supplemen s agains he compa a o s in he subg oups o (a) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and; (b) dialysis pa ien s. C I, c edible in e als; OR, odds a io. Figu e 4. League ables showing ORs and 95% C Is co esponding o he assessed IV i on supplemen s agains he compa a o s in he subg oups o ( a ) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and; (b) dialysis pa ien s. C I, c edible in e als; OR, odds a io. Table 1. SUCRA-based anking o i on supplemen s e alua ed. I on Supplemen s †SUCRA ‡ CKD 3A-5/dialysis § Fe umoxy ol 1020 mg/mo 0.926/0.673 Fe ic ca boxymal ose 750–1500 mg/mo 0.808/NA I on suc ose ≥400 mg/mo 0.598/0.840 I on suc ose 100–300 mg/mo 0.567/0.614 I on isomal oside 500 mg/mo NA/0.615 I on glucona e 1000–1500 mg/mo 0.502/0.439 I on polymal ose 500 mg/mo NA/0.293 Fe ic ca boxymal ose >1500 mg/mo 0.280/NA I on isomal oside 1000 mg/mo 0.248/NA I on P.O. 0.091/0.176 § SUCRA alues a e exp essed o each o he wo subg oups con o med. † I on supplemen s analyzed we e anked acco ding o p obabili ies o being he bes , he second bes , he hi d bes , and so on P( =b) , b= 1, . . . , a ollowing Ma ko chain Mon e Ca lo me hods. ‡ SUCRA o each p epa a ion ou o he acompe ing i on supplemen s equi es calcula ion o he a ec o o he cumula i e p obabili ies cum ,b o be among he b bes d ug, b= 1, . . . , a . Abb e ia ions: CKD, ch onic kidney disease; NA, non-a ailable; P.O., pe os; SUCRA, su ace unde he cumula i e anking a ea. Pha maceu icals 2020,13, 85 6 o 10 Finally, e ec es ima es p esen ed he e should be conside ed as p o ided by a low-quali y body o e idence acco ding o he G ades o Recommenda ion, Assessmen , De elopmen and E alua ion (GRADE) app oach. Quali y a ing ell by wo le els o he e ogenei y and isk o epo ing bias, e en i he e we e no in luence o indi ec ness in e ms o pa icipan s/popula ion, in e en ions, compa a o s and ou comes, no o impo an imp ecision in summa y es ima es (i.e., no wide con idence o c edible in e als). 3. Discussion An adequa e body o e idence suppo s he e icacy o IV i on supplemen a ion be o e and once dialysis is ini ia ed, compa ed o PO i on supplemen a ion. Ne e heless, in e ms o ea men esponse, in CKD pa ien s in o he KDIGO GFR ca ego ies G3A o G5, di e en galenic o ms o i on supplemen a ion a e e icacious, while some a e mo e po en (e.g., e umoxy ol, e ic ca boxymal ose). Clinical implica ions o hese indings may ques ion he use o less po en o mula ions, ne e heless, hey may be used in pa ien s needing o achie e loose goals ( o decide in he clinical a ena). Ou indings lead o an indi idualized ea men app oach o IDA in CKD pa ien s. Despi e conce ns ega ding IV i on supplemen a ion, such as anaphylaxis, bac e ial in ec ions, and a he oscle osis p omo ion [ 21 ], sus ained Hgb le el esponse obse ed in a ious sys ema ic e iews and me a-analyses when compa ed o PO i on supplemen s jus i ies iden i ica ion o he mos pe o ming ones in CKD pa ien s [ 22 – 26 ]. This s udy was, hus, ocused on assessing e idence on he e icacy o hese nanomedicines by examining di e ences in ea men esponse be ween comme cial IV i on supplemen s: pai wise and ne wo k me a-analyses we e ca ied ou o elucida e he indi idual e ec s o hese d ugs ha con o m he main in e en ion o i on supplemen a ion. In ecen yea s, he in oduc ion o new IV i on supplemen s ha e pe mi ed he adminis a ion o la ge doses o i on needed in CKD pa ien s wi h IDA [ 27 ], cons i u ing an impo an a gumen o use less PO i on p epa a ions, e en be o e dialysis [ 4 ]. Ne e heless, as o oday, he e is s ill no conclusi e in o ma ion on he e icacy o hese new p epa a ions in CKD pa ien s: e umoxy ol [ 28 ] and e ic ca boxymal ose [ 29 , 30 ] ha e an impac mos ly on non-selec ed popula ions, acco ding o h ee sys ema ic e iews and me a-analyses, ha may no be disce ned om ha o o he i on supplemen s once glome ula il a ion all o 60 mL/min, as obse ed in ano he i e e idence summa ies s udying CKD popula ions [22–26]. Acco ding o ou indings, e umoxy ol and e ic ca boxymal ose we e associa ed wi h a be e ea men esponse in e ms o Hgb le el inc ease and he absence o he need o o he ea men s o anemia in CKD pa ien s. Such an impac is no ma hema ically compa able wi h ha o o he i on supplemen s. Ou indings p o ide, hus, a solu ion o he need o enla ging he e idence body size conce ning CKD, claimed by e idence summa ies a ew yea s ago [ 25 , 26 , 30 ], and o which his s udy may be conside ed an upda e. This me a-analysis has been ca ied ou acco ding o a planned, egis e ed, and p ospec i ely upda ed sys ema ic e iew p o ocol ollowing cu en ecommenda ions [ 31 ], as a clea signal o main aining anspa ency in he sys ema ic e iew p ocess [ 32 ], a oiding u u e changes, which may be associa ed wi h epo ing biases [ 33 ], and showing he sui abili y and non-duplici y o ou analysis [ 34 ]. Ne e heless, a ious limi a ions should be men ioned. Publica ion bias is mos likely he cause o he obse ed unnel plo asymme y [ 35 ]. Publica ion and o he epo ing biases can lead o o e ly op imis ic conclusions in a me a-analysis [ 36 ]. He e ogenei y should also be aken in o accoun , as conclusions om a me a-analyses a e less clea when he included s udies ha e di e ing esul s [ 37 ]. Fu he mo e, summa y es ima es p esen ed he e included da a om ex ension ollow-up s udies/pos -hoc analyses o some o he eligible RCTs [ 6 – 15 ], which in i e cau ious in e p e a ion, as indings om unplanned analyses a e o lesse alue [ 38 ]. Finally, his me a-analysis includes ials o less han 1000 pa icipan s, so ou indings con ibu e o cla i y alse subs an ial e ec s epo ed by such small ials [ 39 ]: p obably mo e esea ch is needed o deny he absence o e ec s om 1500 mg o Pha maceu icals 2020,13, 85 7 o 10 mo e o e ic ca boxymal ose pe mon h, which was obse ed in he 400 pa icipan s who unde wen hese doses, compa ed o he 3200 pa icipan s using lesse doses. In conclusion, he new IV i on supplemen s e umoxy ol and e ic ca boxymal ose appea o be he bes pe o ming p epa a ions in CKD pa ien s be o e dialysis. Howe e , he o he comme cial i on supplemen s, such as i on suc ose o i on dex an, may con inue o be used, especially in dialysis pa ien s, and in all hose in whom loose goals may be pe mi ed. This s udy did no add ess sa e y conce ns (e.g., anaphylac ic eac ions epo ed wi h e umoxy ol)—i was in ended o measu e e icacy o hese nanomedicines on he basis o ea men esponse. Ou analyses p o ide physicians wi h pa ame e s o adequa ely ollowing up pa ien s equi ing i on supplemen a ion, and indi ec ly by making i possible o iden i y good esponde s among all ea ed wi h hese medicines. E idence-based ea men s a egies may lead o indi idualized ea men s a egies in CKD pa ien s [40]. 4. Ma e ials and Me hods This manusc ip p esen s indings om pai wise and ne wo k me a-analyses ca ied ou in acco dance wi h he PRISMA ecommenda ions [ 31 ], and mee ing he PRISMA ex ension s a emen equi emen s o epo ing o sys ema ic e iews inco po a ing ne wo k me a-analyses o heal hca e in e en ions [ 41 ]. Fo u he de ails o ou me hods and hei p ospec i e cha ac e , ou egis e ed sys ema ic e iew p o ocol (In e na ional p ospec i e egis e o sys ema ic e iews PROSPERO e e ence ID: CRD42020148155) is a ailable o eade s by clicking on he ollowing link: h ps: //www.c d.yo k.ac.uk/p ospe o/display_ eco d.php?ID=CRD42020148155. By using da abase-speci ic sea ch s a egies being de eloped wi h sea ch e ms ela ed o pa icipan s/popula ion, in e en ions, exposu es, and he ype o s udy o be included, MEDLINE ia PubMed, O id and Web o Science, EMBASE ia Else ie ’s Scopus, he Coch ane Con olled Regis e o T ials (CENTRAL), and o he impo an da abases o published s udies ia Web o Science, we e sea ched up o Sep embe 2019. In addi ion, ClinicalT ials.go , he EU Clinical T ials Regis e and he Uni ed Kingdoms’ ISRCTN egis y, and ele an g ay li e a u e sou ces we e sea ched. The e e ence lis s o he included s udies we e scanned o iden i y all ele an s udies ci ed by he included s udies. The li e a u e sea ch was limi ed o he English language. Ou ull sea ch s a egy and sea ch esul s a e a ailable o eade s online (Panel S1). As p e iously desc ibed [ 40 ], ou s a egy was ocused on he iden i ica ion o RCTs including hei ex ension ollow-up s udies, and all a ie ies o pos -hoc analysis ha assessed indi iduals wi h no mal kidney unc ion (NKF)/CKD in o KDIGO GFR ca ego ies G1 and G2, CKD pa ien s in o he KDIGO GFR ca ego ies G3A o G5, ch onic dialysis pa ien s, and kidney ansplan pa ien s. Ne e heless, in his s udy, ou e alua ions we e cen e ed on compa ing e idence o he e icacy o IV and PO i on supplemen s: ou main ou come was ea men esponse, which was de ined by he inc ease in Hgb le el and he need o o he ea men s o anemia in CKD (e.g., ESA he apy o blood ans usion). A e assessing isk o bias in he included s udies [ 42 ], he o e all OR wi h hei 95% con idence in e al (95% CI) o he ou comes o Hgb inc ease o ≥ 0.5–1.0 g/dL and he combined o non- esponse o i on supplemen a ion (i.e., Hgb inc ease o <0.5–1.0 g/dL, o ini ia ion/in ensi ica ion o ESA he apy, o inc ease/change o i on supplemen , o equi emen s o blood ans usion), we e ob ained (Man el–Haenszel andom-e ec me hod), wi h e alua ion o he e ogenei y ( χ2 , I 2 ) and epo ing bias isk ( isual inspec ion o unnel plo s and calcula ion o Egge ’s es , i necessa y) in summa y es ima es. Re iew Manage so wa e (Re Man) e sion 5.3 (Coch ane Collabo a ion) and META-analysis package FO R (METAFOR) e sion 2.4 (R p ojec ) we e used o calcula ions a he pai wise le el. The ea e , OR wi h hei co esponding 95% C I o he combined ou come o non- esponse o i on supplemen a ion we e calcula ed ia Bayesian ne wo k me a-analysis (Ma ko chain Mon e Ca lo simula ion on ague p io s andom-e ec me hod o ‘bad’ ou comes and ze o alues co ec ion), wi h calcula ion o he alue o SUCRA co esponding o each o he i on supplemen s desc ibed in s udies eligible, and wi h e i ica ion o con e gence (B ooks–Gelman–Rubin me hod) and inconsis ency. Ne Me aXL so wa e (Canadian Agency o D ugs and Technologies in Heal h and Co ne s one Resea ch G oup) [ 43 ] was Pha maceu icals 2020,13, 85 8 o 10 used o pe o ming ne wo k me a-analysis. The analysis was pe o med o wo subg oups: 1) pa ien s in KDIGO GFR ca ego ies G3a o G5, and; 2) dialysis pa ien s. Skewed and non-quan i a i e da a was p esen ed desc ip i ely ollowing he ecommenda ions o he Cen e o Re iews and Dissemina ion (Uni e si y o Yo k) [44]. Quali y a ing was pe o med by using GRADE [42]. Supplemen a y Ma e ials: The ollowing a e a ailable online a h p://www.mdpi.com/1424-8247/13/5/85/s1, Table S1: Pa icipan s, in e en ions, compa a o s, and ou comes in (a) he ials ha p o ided nume ical da a o he me a-analysis and (b) he ials ha did no p o ide nume ical da a o he me a-analysis, Table S2: Risk o bias in he eligible s udies, Figu e S1: Inconsis ency plo on andom e ec s o he SUCRA assessable i on supplemen s alues in he subg oups o (a) pa ien s in he KDIGO GFR ca ego ies 3A o 5, and (b) dialysis pa ien s, Panel S1: Sea ch s a egy o mulae and sea ch esul s. Au ho Con ibu ions: Concep ualiza ion, F.H.-G. and M.A.; me hodology, C.O.-S., F.H.-G., and M.A.; so wa e, C.O.-S. and F.H.-G.; alida ion, C.O.-S., F.H.-G., and F.J. Á .; o mal analysis, C.O.-S. and F.H.-G.; in es iga ion, C.O.-S., D.M.-G., F.H.-G., F.J. Á ., M.A., and M.G.; esou ces, F.H.-G. and F.J. Á .; da a cu a ion, D.M.-G., F.H.-G., F.J. Á ., M.A., and M.G.; w i ing—o iginal d a p epa a ion, F.H.-G., F.J. Á ., and M.A.; w i ing— e iew and edi ing, C.O.-S., D.M.-G., F.H.-G., F.J. Á ., M.A., and M.G.; isualiza ion, F.H.-G.; supe ision, C.O.-S. and F.J. Á .; p ojec adminis a ion, F.H.-G. and M.A. a e co- i s au ho s. F.J. Á . and C.O.S. a e co-senio au ho s. All au ho s ha e ead and ag eed o he published e sion o he manusc ip . Funding: This esea ch ecei ed no ex e nal unding. Acknowledgmen s: The au ho s hank B. Muñoz (Clinical Epidemiology Resea ch Suppo O ice, Complejo Asis encial de Zamo a, Zamo a, Spain) who helped coo dina e he da a e ie al. Con lic s o In e es : The au ho s decla e no con lic o in e es . Re e ences 1. Kidney Disease: Imp o ing Global Ou comes (KDIGO) Anemia Wo k G oup. KDIGO clinical p ac ice guideline o anemia in ch onic kidney disease. Kidney In . Suppl. 2012 ,2, 279–335. A ailable online: h ps://kdigo.o g/wp-con en /uploads/2016/10/KDIGO-2012-Anemia-Guideline-English.pd (accessed on 11 Ma ch 2020). 2. Fishbane, S.; Spinowi z, B. 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