Devlopman dwòg ede amelyore alontèm pronostik nefropati IgA
Jul 24, 2023
Nefropati IgA (IgAN) se kounye a glomerulonefrit prensipal ki pi komen nan Lachin e menm nan mond lan. Etid anvan yo te montre ke plis pase yon tyè nan pasyan Chinwa IgAN adilt yo ap pwogrese nan etap final maladi ren (ESKD) nan 20 ane [1]. Kounye a, metòd tretman klinik pou IgAN yo trè limite, e gen yon gwo bezwen klinik ki pa satisfè.
Klike sou òganik cistanche pou maladi ren
Gid Pratik Klinik 2021 pou Jesyon Maladi Glomerulè Òganizasyon pou Amelyore Rezilta ren Global (KDIGO) [2] te fikse sib kontwòl proteinuria pou<1 g/d, but whether there is still room for optimization of this target value still needs more evidence accumulation. The results of a large cohort study recently published by Professor Jonathan Barratt of the University of Leicester in the United Kingdom show that even patients traditionally considered as "low risk", that is, patients with urine protein-to-creatinine ratio (UPCR) <0.88 g/d (equivalent to proteinuria 1 g/d), their risk of developing renal failure within 10 years is still high.
Ki jan yo plis diminye proteinuria nan pasyan IgAN, estabilize fonksyon ren, ak amelyore pronostik alontèm maladi a vin konsantre nan atansyon komen nan doktè ak pasyan yo. Atik sa a baze sou rechèch Pwofesè Jonathan Barratt ak pwogrè rechèch sou dwòg ki gen rapò ak IgAN divilge nan reyinyon anyèl 2023 European Society of Nephrology (ERA). Nou envite ekspè nan domèn nan analize sitiyasyon aktyèl tretman IgAN nan Lachin, gade pou pi devan pou tan kap vini an, ak eksplore solisyon an pi bon nan IgAN.
Dènye rechèch ki baze sou prèv la revele verite a sou pronostik alontèm pasyan IgAN[3]
IgAN se kòz prensipal maladi ren kwonik (CKD) ak ESKD, epi pifò pasyan devlope li nan jèn adilt yo (<40 years old). However, in the current situation where the average life expectancy is >70 ane fin vye granmoun, Lachin toujou manke done evalyasyon alontèm sou pronostik la nan maladi alontèm ki dire pou dè dekad.
Pou pi byen konprann pronostik alontèm pasyan IgAN, Pwofesè Jonathan Barratt, yon nefrologist ki renome nan lemonn, te analize relasyon ki genyen ant proteinuria ak pant estimasyon to filtraj glomerulèr (eGFR) ak risk pou tout lavi ESKD ki baze sou done klinik pasyan IgAN. ki soti nan Rejis Maladi ren Rare (RaDaR). Etid la enkli 2,439 pasyan IgAN (IgAN konfime pa byopsi ren, proteinuri > 0.5 g / d oswa eGFR < 60 ml / min·1.73 ㎡), ki gen ladan 2,299 granmoun ak 140 minè.
Rezilta etid la te montre ke pronostik alontèm pasyan IgAN pa optimis. Apre yon swivi medyàn nan 5.9 ane (3.0-10.5), 50 pousan nan pasyan devlope ESKD oswa mouri. Peryòd siviv ren medyàn lan te 11.4 (10.5-12.5) ane, ak laj mwayèn ESKD/lanmò a te sèlman 48 an.
Dapre eGFR ak laj nan dyagnostik, prèske tout pasyan yo riske pwogresyon maladi a nan ESKD nan esperans lavi yo. Espesyalman, pou pasyan ki gen yon pant eGFR ki pi gran pase oswa egal a 3 ml/min/1.73 m2/ane ak laj nan dyagnostik mwens pase oswa egal a 40 ane, risk pou tout lavi a nan ESKD se 100 pousan; pandan ke pou pasyan ki gen eGFR pant 1 ml / min / 1.73 m2 / ane ak laj nan dyagnostik mwens pase oswa egal a 50 ane, risk pou tout lavi nan ESKD se apeprè 40 pousan.
Etid la plis revele relasyon ki genyen ant proteinuria ak rezilta ren yo. Tan-mwayèn analiz proteinuria te montre ke pi wo a proteinuria tan-mwayèn, pi mal la siviv ren ak pi vit n bès eGFR la. Espesyalman, pasyan IgAN yo ak proteinuria tan-mwayèn nan 0.44-0.88 g / d te gen yon risk 30 pousan nan ESKD nan 10 ane; pasyan ki gen proteinuria tan an mwayèn<0.44 g/d had a 20% risk of ESKD within 10 years.
An patikilye, etid la te note ke pou pasyan sa yo jeneralman konsidere kòm "risk ki ba," sa vle di, proteinuria<0.88 g/d (equivalent to proteinuria 1 g/d), the risk of developing ESKD within 10 years was high and the long-term prognosis was poor. This skinny reality reminds us that the effective prevention and treatment of IgAN still have a long way to go. In the future, the collective efforts of all forces are needed to fundamentally improve the long-term prognosis of IgAN patients.
Q1 Etid kowòt Pwofesè Jonathan Barratt a ki baze sou popilasyon Britanik la te montre ke pifò pasyan IgAN yo ap pwogrese nan ESKD nan 10-15 ane, epi rezilta klinik la jeneralman pòv. Konbine ak done sa yo, èske ou ta ka tanpri pale sou sitiyasyon aktyèl la nan jesyon alontèm pasyan IgAN nan peyi Lachin?
Pwofesè Lu Jicheng:
The data of this study (follow-up up to 30 years) suggest that even the Western population, which is traditionally considered to have a better prognosis for IgAN, has a very different prognosis than imagined. In the past, we generally believed that more than 30% of patients would progress to uremia within 10 to 20 years, but the latest research results of Professor Jonathan Barratt suggest that the prognosis of IgAN patients is worse, and the proportion of patients entering ESKD is as high as 50%, and the enrolled patients (proteinuria>0.5g/d oswa eGFR<60 ml/min·1.73㎡) almost all will progress to renal failure during their lifetime. Based on this challenge, we must update the existing IgAN treatment measures. In addition, although China currently lacks national and multi-center data on the long-term prognosis of IgAN, an early retrospective study of more than 1,000 patients from the Eastern Theater General Hospital showed that more than 1/3 of IgAN patients (average proteinuria 0.9g/d) would progress to ESKD within 20 years; research results from Peking University First Hospital showed that more than 40% of IgAN patients (average proteinuria>1.8g/d) ta pwogrese nan ESKD apre 10 ane.
De etid kòwòt sa yo ki soti nan Lachin sijere ke pronostik la nan pasyan IgAN nan Lachin ka pi mal pase sa yo ki nan pasyan oksidantal yo. Sa fè nou sonje ke nou bezwen travay sou IgAN nan plizyè fason:
1. Optimize estrateji tretman aktyèl la epi ankouraje normalisation dyagnostik ak tretman;
2. Pou amelyore pronostik pasyan yo, kontinye ranfòse rechèch nouvo dwòg;
3. Avanse tan an nan byopsi ren pou reyalize dyagnostik bonè ak tretman otank posib.
Q2 Rezilta rechèch pwofesè Jonathan Barratt montre ke pou pasyan IgAN ki gen "ti risk" ki gen proteinuri<0.88 g/g, the incidence of ESKD is still high within 10 years. What does this suggest for the current management goals of IgAN in China?
Pwofesè Lu Jicheng:
Objektif jesyon pou diminye proteinuri a<0.88g/d (equivalent to 24-hour proteinuria <1g) mainly comes from an early Toronto cohort study. The results of this study showed that reducing proteinuria to <1g/d, <0.5g/d, or even <0.3g/d has no significant difference in clinical outcomes. Based on this research, the current 2021 KDIGO guidelines set the goal of proteinuria control and the inclusion criteria for clinical research as proteinuria <1g/d. However, according to previous studies, the prognosis of IgAN in Easterners is often worse than that in Westerners, and the risk of renal failure increases by more than 80%. Therefore, the current research data reminds us to adjust the control standard of proteinuria, a chronic risk factor for renal failure, to a lower level, that is, at least control UPCR below 0.44g/d (equivalent to 24-hour proteinuria<0.5g).
Q3 Soti nan rechèch Pwofesè Jonathan Barratt, nou konnen ke kontwòl strik nan nivo proteinuria gen gwo siyifikasyon amelyore pronostik alontèm nan pasyan IgAN. Pou pi byen reyalize objektif la pou amelyore pronostik alontèm pasyan yo, ki jan nou ta dwe optimize pratik klinik ak konsepsyon esè?
Pwofesè Lu Jicheng: Pou pi byen kontwole proteinuria nan pasyan yo, nou ka travay sou twa aspè sa yo.
1. Peye atansyon sou jesyon alontèm pasyan yo. Ren a se yon "ògàn an silans", ak pwogresyon maladi souvan rive insansibl, kidonk jesyon maladi pasyan yo pa ka fèt piman baze sou sentòm klinik yo. Pandan jesyon pasyan yo, pasyan yo ta dwe konplètman kominike pou fè yo okouran de enpòtans pou kontwole pwòp tèt ou nan san presyon, siveyans regilye nan pwoteyin urin (omwen chak 3 mwa anba kontwòl ki estab), ak enpòtans ki genyen nan siveyans regilye nan fonksyon ren.
2. Optimize ki baze sou tretman tradisyonèl pou kontwole nivo proteinuria otank posib. Yon etid kòwòt te montre ke optimize estrateji tretman ki deja egziste, tankou rejim alimantè ak kontwòl tansyon, ak bon jan tretman RAS blocker (RASi), ka siyifikativman amelyore proteinuria nan pasyan yo.
3. Peye atansyon sou rechèch ak devlopman nouvo dwòg. Mezi tretman ki deja egziste yo toujou pa kapab satisfè bezwen tretman yo. Dapre rezilta etid TÈS la, risk pou ensifizans renal nan lavni an ogmante pa 7.8 pousan chak ane pou pasyan ki gen proteinuria pa byen kontwole apre tretman sipò, se sa ki, prèske 80 pousan nan pasyan yo ap devlope ensifizans renal nan 10 ane. . Apre terapi òmòn konbine, efè guérison evidan men reyaksyon negatif yo ogmante. Malgre ke terapi òmòn diminye risk pou ensifizans renal pa 40 pousan, risk pou ensifizans renal rezidyèl toujou ogmante pa 4.9 pousan chak ane, se sa ki, 50 pousan nan pasyan toujou devlope ESKD nan 10 ane. Se poutèt sa, nou bezwen ijan dwòg ki pi efikas sou mache a pou redwi rezidyèl 4.9 pousan risk chak ane nan echèk ren a pi ba pase 1 pousan oswa pi ba chak ane.
Q4 Baze sou Syèk Limyè a te pote pa rechèch Pwofesè Jonathan ak dyagnostik klinik aktyèl la ak estati tretman an, ki rechèch dwòg ak direksyon devlopman ou panse ka espere nan lavni an?
Pwofesè Lu Jicheng:
Tretman IgAN tradisyonèl se sitou ki baze sou tretman ki pa espesifik, tankou dwòg antihypertensive, RASi, òmòn, elatriye Koulye a, li baze sou patojèn nan IgAN, ak devlopman nan nouvo dwòg sitou gen ladan twa kategori.
Premye klas dwòg jwe yon wòl terapetik pa anpeche pwodiksyon en IgA, sitou ki gen ladan antikò monoklonal vize ligand pwopagasyon pwovoke (APRIL), vize faktè B selil activation (BAFF) / APRIL inibitè doub, ak imunosuppressants entesten.
Dezyèm klas dwòg vize konpleman. Apre konplèks iminitè a fòme ak depoze nan ren an, li pral aktive konpleman an ak lakòz domaj nan ren yo. Se poutèt sa, yon varyete dwòg vize konpleman yo te aktivman eksplore, sitou ki gen ladan faktè B inibitè LNP023, nukleotid antisans, ak dwòg ki vize mannan-obligatwa lectin-asosye serine proteaz -2 (MASP-2) inhibiteurs.
The first two types of drugs are immunomodulators or immunosuppressants, and the risk of adverse reactions of long-term use needs more data accumulation. The third type of drug is a new target drug for non-specific treatment of kidney injury other than RASi, which can be used as a supportive treatment for a long time to exert a long-term protective effect. Such drugs mainly include endothelin receptor blockers such as Atrasentan, Sparsentan, sodium-glucose cotransporter 2 inhibitors (SGLT2i), etc. Both Atrasentan and Sparsentan have carried out clinical phase 2 and phase 3 trials in IgAN patients, and the results have proved that these drugs are more effective than specific drugs in reducing proteinuria, with an average proteinuria reduction of >40 pousan.
Nou gen rezon pou predi ke nan tan kap vini an, itilizasyon konbine twa kalite dwòg ki anwo yo espere siyifikativman diminye risk pou ensifizans ren rezidyèl nan pasyan ki gen IgAN.
Gade espwa nan pwogrè dwòg IgAN ERA 2023
Malgre ke sitiyasyon an nan kontwòl nefropati IgAN se toujou mèg, dimanch maten byen bonè nan espwa ap flache pi devan. Nan 60yèm ERA Kongrè a ki te fèt an 2023, rechèch sou nouvo dwòg ki vize plizyè sib pou amelyore tretman IgAN kontinye ap parèt.
Li se itilize nan sous la nan "kadruple frape" yo vize pwodiksyon an nan en Gd-IgA, e li te atire anpil atansyon kòm yon dwòg ki ka geri ou. Zigakibart (BION-1301), yon nouvo antikò monoklonal imanize (mAb) ki mare ak bloke APRIL, te pibliye [4] Rezilta analiz pwovizwa yo nan dènye etid klinik faz I/II te montre ke nan tout pasyan nan konbine an. analiz kowòt 1 ak 2, tretman BION-1301 te kapab redwi proteinuria pa yon mwayèn de 20 pousan nan 12 semèn, 39 pousan nan 24 semèn, ak 67 pousan nan 52 semèn. An menm tan an, etid la te montre tou ke tretman pwolonje ak BION-1301 ka pote benefis klinik soutni pasyan yo: nan 76 semèn nan tretman, an mwayèn proteinuria nan 7 pasyan diminye pa 67 pousan; nan 100 semèn nan tretman an, proteinuria an mwayèn nan 5 pasyan diminye pa 72 pousan.
Dwòg la VIS649, ki se tou yon antikò monoklonal anti-APRIL, te montre tou yon bon efikasite nan diminye proteinuria. Rezilta analiz pwovizwa etid Faz II li yo te montre ke, konpare ak gwoup plasebo a, tretman VIS649 pou 36 semèn redwi siyifikativman proteinuria pa 43 pousan [5].
Anplis de sa, rezilta etid klinik la faz 2b (ORIJINE) nan faktè a aktive selil B (BAFF) / APRIL doub inibitè Atacicept nan tretman pasyan IgAN te montre ke apre 36 semèn nan tretman Atacicept, chanjman yo nan proteinuria evalye pa UPCR. yo te redwi pa yon mwayèn de 35 pousan konpare ak debaz [6].
2-Rezilta swivi ane a nan etid Faz III NeflgArd nan budesonide kapsil lage reta pou iminite entesten (Nefecon) te montre ke konpare ak gwoup la plasebo, gwoup la Nefecon 16mg te gen yon UPCR siyifikativman pi ba nan debaz (30.7). pousan vs 1 pousan )[7], ak yon bès siyifikativman pi ba nan eGFR soti nan debaz (-6.11 vs -12.00 ml/min·1.73 ㎡, P<0.0001).
Atrasentan, ki vize ak bloke reseptè endothelin tip A (ETA), se yon dwòg rechèch ki te atire anpil atansyon nan domèn nan. Nan konferans ERA sa a, yo te anonse konsepsyon etid ASSIST ki tap eksplore terapi konbinezon Atrasantan ak SGLT2i [8], ki espere plis anrichi estrateji ki pa iminoterapi pou IgAN. Atrasentan se yon nouvo dwòg pwomèt pou IgAN. Rezilta etid klinik faz II li yo (AFFINITY) montre ke Atrasentan ka kontinyèlman ak siyifikativman diminye proteinuria, ak yon rediksyon mwayèn nan proteinuria pa 54.7 pousan apre 24 semèn nan tretman, epi li an sekirite epi byen tolere[9].
Etid kowòt pwofesè Jonathan Barratt te ban nou anpil bagay pou nou reflechi. Etid sa a montre ke tradisyonèlman konsidere kòm "ki ba-risk" pasyan ki gen proteinuria<0.88 g/d are still at high risk of developing ESKD within 10 years. This suggests that the current prevention and control status of IgAN patients in my country still has a large gap with the target. To better control proteinuria and improve the long-term prognosis of IgAN patients, we need to diagnose as early as possible, optimize existing treatment strategies, strengthen long-term management of blood pressure, proteinuria, and renal function in patients, and adjust the control target of proteinuria to a lower level. Due to the limited existing treatment measures, traditional treatment can no longer meet the current treatment needs, so we urgently need new drugs to be launched.
Kounye a, yon varyete nouvo dwòg ak diferan mekanis pote nou espwa. Medikaman sa yo genyen ladan yo vize antikò monoklonal APRIL, inibitè doub BAFF/APRIL, ak imunodepresè entesten ki anpeche pwodiksyon IgA en; vize konpleman dwòg-faktè B inhibiteurs ak vize MASP-2 inhibiteurs; nouvo dwòg ki pa espesifik ki ka itilize pou alontèm tretman-endothelin reseptè blockers Atrasentan, Sparsentan, ak SGLT2i, elatriye dwòg sa yo te montre bon efikasite nan diminye proteinuria nan rechèch la. Yo kwè ke ak devlopman nan plis etid klinik, plis nouvo dwòg pral antre nan aplikasyon klinik, ki se mare nan "kraze" dilèm tretman aktyèl la nan IgAN ak amelyore pronostik alontèm nan pasyan IgAN.
Referans:
[1]Le W, et al. Nephrol Dial transplantasyon. 2012 Apr;27(4):1479-1485.
[2] 2021 Improve Kidney Outcomes Global Organization (KDIGO) Gid Pratik Klinik pou Nefropati IgA.
[3]Pitcher D, et al. Clin J Am Soc Nephrol. 13 avril 2023.
[4] Apre "maryaj la" ak Novartis, Chinook te pote de baz debaz nan "eksploze jaden an" reyinyon anyèl ERA. Kib Rubik Medsin, 2023.6.21. https://mp.weixin.qq.com/s/82OJsDurjmLk7y0UrfRG3A
[5]Kieran McCafferty, et al. Repons Vaksen Covid Pandan Tretman Sibeprenlimab nan Nefropati IgA (IgAN): Yon Analiz Pwovizwa. Prezante nan ERA2023.
[6]Richard Lafayette, et al. 36-Semèn Efikasite ak Sekirite Atacicept 150 mg nan etid Faz 2b ORIGIN randomized, Double-avèg, ak plasebo-kontwole nan IgAN ak Proteinuria Persistent. Prezante nan ERA2023.
[7]Richard Lafayette, et al. Benefis ren alontèm sou 2 zan ak Nefecon verifye: rezilta esè konplè NefIgArd Faz III a. Prezante nan ERA2023.
[8]Hiddo Lambers Heerspink, et al. Konsepsyon etid ASSIST: Yon etid randomize, doub-avèg, ki kontwole ak plasebo, kwazman nan Atrasentan nan pasyan ki gen Nefropati IgA (IgAN) sou SGLT2i. Prezante nan ERA2023.
[9]2022ASNKW.RESUM:TH-PO497.
[10] WCN'23 pidevan eksprime 丨 3 rezilta rechèch enpòtan yo mete ajou, epi enspirasyon klinik kontinye. Yimaitong. 2023.4.10. https://news.medlive.cn/neph/info-progress/show-198543_161.html
