Data on a new biomarker for kidney transplant recipients: The number of FoxP3 regulatory T cells in the circulation

Da a A icle Da a on a new bioma ke o kidney ansplan ecipien s: The numbe o FoxP3 egula o y T cells in he ci cula ion F ancisco He e a-Gómez a,b, n ,1 , Waldo del Aguila c , A mando Teje o-Ped egosa d , Ma cel Adle e , Rosa io Padilla-Be dugo a , Ál a o Mau ua-B iseño-Meiggs , Julio Pascual g , Manuel Pascual h , Da id San Segundo i , Sebas iaan Heid j , F. Ja ie Ál a ez a,k , Ca los Ochoa-Sang ado l , Claude Lambe m a Pha macology and The apeu ics, Facul y o Medicine, Uni e si y o Valladolid, Valladolid, Spain b Neph ology, Hospi al Vi gen de la Concha –Sanidad de Cas illa y León, Zamo a, Spain c In e nal Medicine, Kliniken No dobe p alz AG, Baye n, Ge many d In ensi e Ca e Medicine, Hospi al Vi gen de la Concha –Sanidad de Cas illa y León, Zamo a, Spain e Hema ology Se ice and Main Hema ology Labo a o y, Cen e Hospi alie Uni e si ai e Vaudois, Lausanne, Swi ze land Woodland Medical P ac ice –NHS, Lincolnshi e, Uni ed Kingdom g Neph ology, Hospi al del Ma , Ba celona, Spain h Cen e de T ansplan a ion d'O ganes, Cen e Hospi alie Uni e si ai e Vaudois, Lausanne, Swi ze land i Immunology, Hospi al Uni e si a io Ma qués de Valdecilla, San ande , Spain j Immunohaema ology and Blood T ans usion, Leiden Uni e si y Medical Cen e , Leiden, he Ne he lands k CEIm Á ea de Salud Valladolid Es e, Hospi al Clínico Uni e si a io de Valladolid, Valladolid, Spain l Clinical Epidemiology Resea ch Suppo , Sanidad de Cas illa y León, Zamo a, Spain m Immunology, Cen e Hospi alie Uni e si ai e de Sain -E ienne, Sain -P ies -en-Ja ez, F ance a icle in o A icle his o y: Recei ed 22 Oc obe 2018 Recei ed in e ised o m 15 No embe 2018 Accep ed 16 No embe 2018 A ailable online 27 No embe 2018 abs ac This a icle p esen s un e ealed de ails o he sys ema ic e iew p ocess o he a icle “The numbe o FoxP3 egula o y T cells in he ci cula ion may be a p edic i e bioma ke o kidney ans- plan ecipien s: A mul is age sys ema ic e iew”(He e a-Gómez e al., 2018). Eligibili y c i e ia guiding sea ches and s udy selec- ion, he isk o bias assessmen , he assessmen o medicine- es Con en s lis s a ailable a ScienceDi ec jou nal homepage: www.else ie .com/loca e/dib Da a in B ie h ps://doi.o g/10.1016/j.dib.2018.11.083 2352-3409/&2018 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/). DOI o o iginal a icle: h ps://doi.o g/10.1016/j.in imp.2018.10.028 n Co espondence o: Depa men o Pha macology and The apeu ics, Facul y o Medicine, Uni e si y o Valladolid, A enida Ramón y Cajal, 7, 47005 Valladolid, Spain. Fax: þ34983423022. E-mail add ess: [email p o ec ed] (F. He e a-Gómez). 1 ORCID: www.o cid.o g/0000–0002-3110-692X. Da a in B ie 21 (2018) 2567–2575 codependency (e alua ion o he body o e idence), and me a- analy ic calcula ions a e p o ided. The da a allows o he esea che s, pa icula ly hose in ol ed in expe imen s on T ans- la ional Epidemiology applied o Pha macology, o co obo a e and ex end ou assessmen s. &2018 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/). Specifica ions able Subjec a ea Biology Mo e specific subjec a ea T ansla ional pha macology Type o da a Tex , ables, and figu es. How da a was acqui ed Defini ion o eligibili y c i e ia and sea ch s a egy o s udy selec- ion, isk o bias assessmen , assessmen o codependen heal h echnologies, and me a-analy ic assessmen . Da a Fo ma Raw and analyzed. Expe imen al ac o s Sys ema ic e iew p o ocol egis a ion, s udy selec ion p ocess (agains eligibili y c i e ia), and da a ex ac ion. Expe imen al ea u es Inclusion and exclusion c i e ia, ull sea ch s a egy, isk o bias assessmen , assessmen o medicine– es codependency, and con- inuous da a me a-analysis. Da a sou ce loca ion Valladolid, Spain, 41.654444°,4.7175° Da a accessibili y Da a is wi h his a icle. Rela ed esea ch a icle F. He e a-Gómez, W. del Aguila, A. Teje o-Ped egosa, M. Adle , R. Padilla-Be dugo, A. Mau ua-B iseño-Meiggs, Julio Pascual, Manuel Pascual, Da id San Segundo, Sebas iaan Heid , Ja ie Ál a ez, Ca los Ochoa-Sang ado , Claude Lambe , The Numbe o FoxP3 Regula o y T Cells in The Ci cula ion May Be a P edic i e Bioma ke o Kidney T ansplan Recipien s: A Mul is age Sys ema ic Re iew, In . Immu- nopha macol. 65 (2018) 483–492 [1] Value o he da a  In he field o T ansla ional Pha macology, sha ing sys ema ic e iew p ocess de ails is e y impo an .  This da a allows o he esea che s o co obo a e and ex end ou assessmen s.  The main aim o sha ing his da a is o imp o e he qualifica ion o po en ial p edic i e bioma ke s. 1. Da a In addi ion o links o he ou sys ema ic e iew p o ocols egis e ed in he In e na ional P o- spec i e Regis e o Sys ema ic Re iews (PROSPERO) (Appendix A. Supplemen a y ma e ial. Tex S1), his a icle p esen s he inclusion and exclusion c i e ia ( Tables 1 and 2), he en i e sea ch s a egy o he sys ema ic e iews pe o med (Appendix A. Supplemen a y ma e ial. Tex S2), he isk o bias (quali y) assessmen de ails (Tables 3–5), he assessmen o medicine– es codependency (Table 6), and he me a-analyses (Figs. 1–3) we e no included in he a icle o He e a-Gómez e al. [1]. F. He e a-Gómez e al. / Da a in B ie 21 (2018) 2567–25752568 Table 1 Re iew ques ions and s udy eligibili y o each o he 4 sys ema ic e iews. Sys ema ic mapping/sys ema ic e iew suppo o In-dep h sys ema ic e iew/sys ema ic e iew suppo o Re iew ques ions a Wha a e he changes in he pe iphe al blood immune pheno ype ha a e associa ed wi h COT b ? c Wha e ec does he inc eased equency o egula o y cells in he ci cula ion in KTRs and LTRs ha e on AR/ AAD when using mTORi wi h/wi hou BELA? c Which ole ance-associa ed blood cells o eg- ula o y cells inc ease in he ci cula ion in KTOLs and LTOLs d ? e Wha e ec does he inc ease in T egs in he ci cula- ion unde mTORi-based IS ha e on AR/AAD in KTRs? Is he e an inc eased equency o T egs in he ci cula ion g in KTOLs? e Wha is he e ec o mTORi-based IS on he numbe o T egs in he ci cula ion in KTRs? Wha is he e ec on AR/AAD ha co esponds o an inc eased equency o T egs in he ci cula ion in KTRs when using mTORi wi h/wi hou BELA? Pa icipan s/ popula ion a Pedia ic and adul SOTRs. e Adul KTRs. c Adul KTRs o LTRs. c Adul KTRs o LTRs. Adul KTRs. Adul KTRs. In e en ion (s)/expo- su es(s) a COT c The inc ease in egula o y cells in he ci cula ion g unde mTORi- o mTORi—BELA-based IS. c The inc ease in egula o y cells in he ci cula ion g . The inc ease in T egs in he ci cula ion g . e mTORi-based IS. The inc ease in T egs in he ci cula ion g unde mTORi- o mTORi—BELA-based IS. Compa a o s a ISDs including KTRs wi h CR. c Dec eased/unchanged numbe s o egula o y cells in he ci cula ion g unde CNI- o BELA-based IS. c Dec eased/unchanged numbe s o egula o y cells in he ci cula ion g . e CNI-based IS Dec eased/unchanged numbe s o T egs in he ci cula ion g . Dec eased/unchanged numbe s o T egs in he ci cula ion g unde CNI- o BELA-based IS. Ou comes a Regula o y cells ha inc ease in KTOLs, LTOLs and o he ole an SOTRs. c,e, Less AR/AAD e en s. c, COT. e The inc ease in T egs in he ci cula ion. S udy design P ognos ic s udies h RCT Abb e ia ions: AR/AAD, acu e ejec ion-associa ed acu e allog a dys unc ion; BELA, bela acep ; CNI, calcineu in inhibi o ; COT, clinical ope a ional ole ance; CR, ch onic ejec ion; IS, immunosupp ession; ISD, immunosupp ession dependen eci- pien ; KTOL, ole an kidney ecipien ; KTR, kidney ansplan ecipien ; LTOL, ole an li e ecipien ; LTR, li e ansplan ecipien ; mTORi, mammalian Ta ge O Rapamycin inhibi o ; RCT, andomized con olled ial; SOTR, solid o gan ansplan ecipien ; T eg, FoxP3 egula o y T cell. a One-s age sys ema ic e iew o suppo he co e sys ema ic mapping (CRD42018084941). b The s a e in which ecipien s exhibi s a well- unc ioning g a and lacks his ological signs o ejec ion a e being com- ple ely o all immunosupp ession o a leas 1 yea . c Co e wo-s age sys ema ic e iew cons i u ed o a sys ema ic mapping ollowed by an in-dep h sys ema ic e iew (CRD42017057570). d Inc eased equency o T egs in he ci cula ion a e obse ed in KTOLs and LTOLs, an inc ease in ansi ional B cells and o he B cells a e seen only in KTOLs, and inc eased γδ T cells a e obse ed only in LTOLs. e One-s age sys ema ic e iew o suppo he co e in-dep h sys ema ic e iew (CRD42018085186). In- ocus wo-s age sys ema ic e iew o he same design as he co e wo-s age sys ema ic e iew (CRD4201808085019). g Inc eased and dec eased numbe s o cells o each egula o y cell popula ion we e defined by he au ho s o he included s udies acco ding o ma ke se s o he flow cy ome ic analysis o hese popula ions. h P ospec i e and e ospec i e compa a i e coho s udies. F. He e a-Gómez e al. / Da a in B ie 21 (2018) 2567–2575 2569 Table 2 Exclusion c i e ia. O e all  in i o (animal) and in- i o s udies  Non-sys ema ic and sys ema ic e iews Sys ema ic mapping/sys ema ic e iew suppo o Only in ol ing KTRs:  No analysis o immune cell pheno ypes (flow cy ome y)  RCTs In-dep h sys ema ic e iew/sys ema ic e iew suppo o Only in ol ing KTRs:  No quan ifica ion o T egs (flow cy ome y)  No CNI in con ol g oups  No measu emen o he ou come o AAD  Compa a i e and non-compa a i e coho (obse a ional) s udies Abb e ia ions: AAD, acu e allog a dys unc ion; CNI, calcineu in inhibi o ; KTR, kidney ansplan ecipien ; RCT, andomized con olled ial; T eg, FoxP3 egula o y T cell. Table 3 Ope a ionaliza ion o he QUIPS ool bias i ems o assessing isk o bias in p ognos ic s udies. Po en ial bias I ems o be conside ed o assessmen po en ial oppo u- ni ies o bias S udy pa icipa ionThe s udy sample adequa ely ep e- sen s he popula ion o in e es .  The e is adequa e pa icipa ion in he s udy by eligible indi iduals (kidney ecipien s).  The sou ce popula ion o popula ion o in e es is adequa ely desc ibed (demog aphic and ansplan a ion de ails).  The sampling ame and ec ui men , pe iod o ec ui men , and place o ec ui men (se ing and geog aphic loca ion) a e adequa ely desc ibed.  Inclusion and exclusion c i e ia a e adequa ely desc ibed. S udy a i ionThe s udy da a a ailable (i.e., pa icipan s no los o ollow-up) adequa ely ep esen s he s udy sample.  Response a e (i.e., p opo ion o s udy sample comple ing he s udy and p o iding ou come da a) is adequa e.  A emp s o collec in o ma ion on pa icipan s who d op- ped ou o he s udy a e desc ibed, and easons o loss o ollow-up a e p o ided.  Pa icipan s los o ollow-up a e adequa ely desc ibed P ognos ic ac o measu emen  A clea defini ion o desc ip ion o he p ognos ic ac o measu ed (i.e., he changes in he immune pheno ype asso- cia ed wi h ope a ional ole ance) is p o ided.  Con inuous a iables a e epo ed and app op ia e (i.e., no da a-dependen ) cu -poin s a e used.  The p ognos ic ac o measu emen and me hods a e ade- qua ely alid and eliable.  An adequa e p opo ion o he s udy sample has comple e da a o he p ognos ic ac o .  The me hod and se ing o measu emen a e he same o all s udy pa icipan s. The p ognos ic ac o o in e es is measu ed simila ly o all pa icipan s. Ou come measu emen  A clea defini ion o he ou come o in e es (i.e., clinical ope a ional ole ance a e kidney ansplan a ion) is p o ided.  The ou come measu es and me hods used a e adequa ely alid and eliable (and may include cha ac e is ics, such as blind measu emen and confi ma ion o ou come wi h a alid and eliable es ).  The me hod and se ing o measu emen a e he same o all s udy pa icipan s. The ou come o in e es is measu ed simila ly o all pa icipan s. F. He e a-Gómez e al. / Da a in B ie 21 (2018) 2567–25752570 2. Expe imen al design, ma e ials and me hods Fo s udy selec ion, defini ion o inclusion and exclusion c i e ia and he ull sea ch s a egy we e based on he PICOS elemen s (pa icipan s/popula ion, in e en ion(s)/exposu e(s), compa a o s, ou comes and s udy design) [1]. The ope a ionaliza ion o he Quali y in P ognosis S udies (QUIPS) ool was necessa y (Table 3)[2,3]. Ne e heless, o he isk o bias assessmen , he QUIPS ool and he Coch ane Collabo a ion ool [4] we e used when app op ia e. Fo he assessmen o medicine– es Table 3 (con inued) Po en ial bias I ems o be conside ed o assessmen po en ial oppo u- ni ies o bias Con ounding measu emen and accoun  All con ounde s, including ea men s, a e measu ed.  Clea defini ions o he impo an con ounde s measu ed a e p o ided (e.g., including dose, le el, and du a ion o exposu es).  The measu emen o all impo an con ounde s is ade- qua ely alid and eliable.  The me hod and se ing o con ounding measu emen is he same o all s udy pa icipan s.  App op ia e me hods a e used i impu a ion is used o missing con ounde da a.  Impo an po en ial con ounde s a e accoun ed o in he s udy design (e.g., ma ching o key a iables, s a ifica ion, and ini ial assembly o compa able g oups).  Impo an po en ial con ounde s a e accoun ed o in he analysis (e.g., app op ia e adjus men ). Impo an po en ial con ounding ac o s a e app o- p ia ely accoun ed o S a is ical analysis and epo ing  The e is su ficien p esen a ion o da a o assess he ade- quacy o he analysis.  The s a egy o model building (i.e., inclusion o a iables) is app op ia e and is based on a concep ual amewo k o model.  The selec ed model is adequa e o he design o he s udy.  The e is no selec i e epo ing o esul s. The s a is ical analysis is app op ia e, and all p ima y ou comes a e epo ed Table 4 Assessing isk o bias in eligible p ognos ic s udies eligible using he QUIPS ool. S udies S udy pa i- cipa ion S udy a i ion P ognos ic ac o measu emen Ou come measu emen Con ounding mea- su emen and accoun S a is ical analy- sis and epo ing King's College London s udy b Low isk o bias Mode a e isk o bias High isk o bias Low isk o bias High isk o bias Low isk o bias ITN507 (FACTOR) c Low isk o bias Mode a e isk o bias High isk o bias Low isk o bias High isk o bias Low isk o bias Nan es s udy d Low isk o bias Mode a e isk o bias Mode a e isk o bias Low isk o bias High isk o bias Low isk o bias BMOTS a Low isk o bias Low isk o bias Mode a e isk o bias Low isk o bias High isk o bias Low isk o bias Abb e ia ions: INSERM, Ins i u Na ional de la San é E de la Reche che Médicale; IOT, Indices O Tole ance; ITN, Immune Tole ance Ne wo k. a BMOTS, he B azilian Mul icen e Ope a ional Tole ance s udy. b IOT conso ium s udy. c ITN s udy. d INSERM s udy. F. He e a-Gómez e al. / Da a in B ie 21 (2018) 2567–2575 2571 Table 5 Assessing isk o bias in eligible ials eligible using he Coch ane isk o bias ool. T ials Random sequence gene a ion Alloca ion concealmen Blinding o pa icipan s and pe sonnel Blinding o ou come assessmen Incomple e ou - come da a Selec i e epo ing O he bias Ma io Neg i Ins i u e s udy Low isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Low isk o bias Unclea isk o bias Low isk o bias Hôpi al Edoua d He io s udy Low isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Unclea isk o bias Unclea isk o bias Unclea isk o bias Chandiga h s udy Low isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Uni e si y o Foggia s udy Low isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Unclea isk o bias Unclea isk o bias Low isk o bias IRCCS Policlinico S. Ma eo s udy a Low isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Low isk o bias Low isk o bias Low isk o bias BMS-224818 s udy b Low isk o bias Low isk o bias Unclea isk o bias Unclea isk o bias Low isk o bias Low isk o bias Unclea isk o bias Abb e ia ions: IRCCS, Is i u o di ico e o e cu a a ca a e e scien ifico. a Fondazione IRCCS Policlinico San Ma eo s udy. b B is ol-Mye s Squibb s udy. F. He e a-Gómez e al. / Da a in B ie 21 (2018) 2567–25752572 Table 6 Adap a ion o he Me lin's ool o assess codependency in he combina ion o ea men and es . In o ma ion eques s Commen s Sec ion 1 –Con ex De ails abou he bioma ke , he es and he medicine 1 (O) Cu en eimbu semen a angemen s. The medicines and he es a e a o dable in de eloped coun ies, and a e a ailable in mo e and mo e de eloping coun ies. 2 (T) Tes sponso . Bec on, Dickinson and Company (BD). 3 (M) Medicine sponso . SIR (Pfize : Rapamune s ). BELA (B is ol-Mye s-Squibb: Nulojix s ) 4 (O) Bioma ke . The numbe o T egs in he ci cula ion. 5 (T) P oposed es . Quan ifica ion o ci cula ing T egs by flow cy ome y 6 (O) Medical condi ion o p oblem being managed. AR/AADs in KTRs. 7 (O) Clinical managemen pa hways. Moni o ing o pa ien s. Ra ionale o he codependency 8 (O) Defini ion o he bioma ke . Inc eased/dec eased T egs in he ci cula ion. 9 (O) Biological a ionale o a ge ing specific bio- ma ke (s). Pa ien s wi h inc eased T egs p esen ed less equen AR/AADs. 10 (O) O he bioma ke (s) o assess ea men e ec o he medicine. None. 11(O) P e alence o he condi ion being a ge ed in he popula ion ha is likely o ecei e he es . 10% P oposed impac o codependen echnologies on cu en clinical p ac ice 12 (T) Consis ency o he es esul s o e ime. Inc eased T egs a e obse ed p e e en ially in KTRs ecei ing mTORi wi h/wi hou BELA. 13 (T) Use o he p oposed es wi h o he ea men s and/o o o he pu poses. NA 14 (T) Use o he es in he clinical managemen pa hway. The es is mos likely o be an addi ional es o managing pa ien s. 15 (T) P o ision o he es . The es is ou inely used in hospi als o de eloped coun ies. 16 (T) Specimen o sample collec ion. Pe iphe al blood. 17 (T) Use o he es o moni o ing pu poses (i ele an ) De ec ion o pa ien s a high isk o AR/AADs. 18(O) A ailabili y o o he es s o he bioma ke . None. Sec ion 2 –Clinical e alua ion Di ec e idence app oach Sec ion 2a E idence o p ognos ic e ec o he bioma ke 19(O) P ognos ic e ec o he bioma ke . I can be assumed me hodologically. Sec ion 2d Clinical e alua ion o he codependen echnologies (combined) 20(O) Selec ion o he di ec e idence. Low-le el di ec e idence is a ailable ( e ospec i e bioma ke - s a ified ials). 21(O) Quali y o he di ec e idence. The e idence is o adequa e quali y. I em numbe s a e agged wi h (T), (M) o (O), which indica e whe he he i em numbe is ele an o he es , he medicine o o e laps bo h. Abb e ia ions: AR/AAD, acu e ejec ion-associa ed acu e allog a dys unc ion; BELA, bela acep ; mTORi, mammalian Ta ge O Rapamycin inhibi o ; KTR, kidney ansplan ecipien ; SIR, si olimus. Fig. 1. Inc ease in T egs a 3–6 mon hs pos - ansplan a ion. CI, confidence in e al; CNI, calcineu in inhibi o ; IV, in e se a iance; mTORi, mammalian Ta ge o Rapamycin inhibi o ; ST, s anda d de ia ion; T egs, FoxP3 egula o y T cell. F. He e a-Gómez e al. / Da a in B ie 21 (2018) 2567–2575 2573 codependency, an adap a ion o Me lin's ool included in he guidelines o p epa ing a submission o he Pha maceu ical Benefi s Ad iso y Commi ee (PBAC) om he Depa men o heal h o Aus alia was used [5,6]. Finally, me a-analy ic calcula ions on con inuous ou comes (s anda dized mean- di e ence e ec sizes ob ained unde in e se a iance andom-e ec s model) we e pe o med. Acknowledgemen s The au ho s hank he Conseje ía de Educación, Jun a de Cas illa y León, Spain ( e e ence: VA161G18), o co e ing he publica ion cos s o his a icle. T anspa ency documen . Suppo ing in o ma ion T anspa ency da a associa ed wi h his a icle can be ound in he online e sion a h ps://doi.o g/ 10.1016/j.dib.2018.11.083. Appendix A. Suppo ing in o ma ion Supplemen a y da a associa ed wi h his a icle can be ound in he online e sion a h ps://doi. o g/10.1016/j.dib.2018.11.083. Fig. 2. Inc ease in T egs a 12 mon hs pos - ansplan a ion. CI, confidence in e al; CNI, calcineu in inhibi o ; IV, in e se a iance; mTORi, mammalian Ta ge o Rapamycin inhibi o ; ST, s anda d de ia ion; T egs, FoxP3 egula o y T cell. Fig. 3. Inc ease in T egs a 24 mon hs pos - ansplan a ion. CI, confidence in e al; CNI, calcineu in inhibi o ; IV, in e se a iance; mTORi, mammalian Ta ge o Rapamycin inhibi o ; ST, s anda d de ia ion; T egs, FoxP3 egula o y T cell. F. 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