Kev Pom Zoo Ntawm Nonsteroidal Mineralocorticoid Receptor Antagonism hauv Ntshav Qab Zib Kab Mob

Keeb kwm

Mob ntshav qab zibyog qhov ua rau ESKD thoob ntiaj teb. Nws kwv yees tias 30% ntawm cov neeg mob ntshav qab zib hom 1 thiab 40% ntawm cov neeg muajmob ntshav qab zib hom 2mellitus (T2DM) tsim kab mob raum (1). Kev tuag ntsig txogmob ntshav qab zib raum(DKD) siab dua piv nrog lwm hom CKD (2). Qhov kev tuag no feem ntau yog tshwm sim los ntawmkab mob plawv (CV)., thiab feem ntau cov neeg mob nrogDKDyuav tuag yam tsis muaj kev vam meejESKD(1). Yog li, qhov tsis xav tau kev kho mob uas txo cov kev pheej hmoo ntawm DKD yog qhov loj heev.

Nyem qhov no kom tau txais CISTANCHE rau CKD

Mechanisms of Action of Mineralocorticoid Antagonism nyob rau hauv Diabetic raum

Cov mechanisms uas ua rau ntshav qab zibkab mob raumyog myriad. Kev hloov pauv hemodynamic, cuam tshuam metabolic, proinflammatory, thiab profibrotic processes culminate nyob rau hauv cov qauv kev hloov nyob rau hauv lub raum. Cov cim tseem ceeb ntawm DKD suav nrog glomerular hypertrophy, glomerular hauv qab daus daim nyias nyias nyias thiab nthuav dav mesangial, glomerulosclerosis, tubulointerstitial fibrosis thiab o, thiab arteriosclerosis (1). Nyob rau hauv xyoo tas los no, peb cov armamentarium los kho DKD tau nce ntxiv nrog kev sib ntxiv ntawm sodium-glucose cotransporter -2 (SGLT-2) inhibitors thiab, tsis ntev los no, nrog nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone. MRs yog physiologic binding qhov chaw rau aldosterone, cortisol, thiab, rau qhov tsawg dua, progesterone. Lawv tau nthuav tawm nyob rau hauv ntau lub hlwb ntawm lub raum, suav nrog cov hlwb epithelial ntawm cov hlab ntim, podocytes, mesangial hlwb, tubulointerstitial fibroblasts, thiab macrophages (Daim duab 1). Hauv kev sau cov duct, MR ua kom txhawb nqa sodium reuptake, potassium secretion, thiab kua dej tuav. Hauv cov hlwb uas tsis muaj lub hlwb, MR tswj kev qhia ntawm ntau yam proinflammatory thiab profibrotic genes cuam tshuam nrog DKD kev loj hlob. MR tuaj yeem ua rau tsis tsim nyog nyob rau hauv DKD, ua rau muaj zog NADPH oxidase kev ua haujlwm thiab kev tswj hwm ntawm proinflammatory cytokines (piv txwv li, TNF-a, IL-1b) thiab profibrotic proteins (xws li, cov ntaub so ntswg loj hlob zoo, hloov kev loj hlob b1, plasminogen activator inhibitor 1, matrix metalloproteinase 2). Qhov kev puas tsuaj tshwm sim hauv glomerulosclerosis thiab kev raug mob tubulointerstitial (3).

Finerenone txoj kev khi rau MR hloov nws txoj kev teeb tsa xws li ligands (piv txwv li, aldosterone) tsis tuaj yeem khi, uas tiv thaiv downstream transcription ntawm proinflammatory thiab profibrotic yam (Daim duab 1) (3). Finerenone muaj qhov sib txawv ntawm cov tshuaj pharmacokinetics thiab cov teebmeem physiologic piv nrog steroidal mineralocorticoid antagonists uas cuam tshuam rau kev kho mob rauDKDthiab poov tshuaj. Tsis zoo li cov steroidal MRAs (spironolactone thiab eplerenone), cov nonsteroidal MRA fifinerenone muaj ntau dua xaiv rau MR thiab ua raws li tus inverse agonist, whereas steroidal MRAs ua raws li ib feem agonists. Yog li, fifinerenone thaiv kev ua kom cov receptor thaum tsis muaj ligand nrog kev cuam tshuam ntau dua ntawm kev nrhiav neeg ua haujlwm ntawm transcriptional cofactors (4). Ntawm cov koob tshuaj natriuretic sib piv, fifinerenone muab ntau zog inhibition ntawm proinflammatory thiab profibrotic noob nyob rau hauv lub raum tshaj spironolactone los yog eplerenone. Nws kuj muaj tsawg dua hyperkalemia. Cov teebmeem uas nyiam tsawg dua hyperkalemia nrog fifinerenone suav nrog nws luv luv ib nrab-lub neej, tsis muaj cov metabolites nquag, kev sib npaug ntawm MR xaiv ntawm lub raum thiab lub plawv, thiab tsawg dua epithelial sodium channel upregulation (5). Tsis tas li ntawd, tsis zoo li steroidal MRAs, fifinerenone kuj khi rau mutant MR S180L, ib qho receptor uas yog paradoxically qhib los ntawm progesterone, uas feem ntau yog MR antagonist, ua rau gestational hypertension los yog mob ntshav siab thaum cev xeeb tub. Cov cuab yeej tshwj xeeb no qhia tias nws muaj peev xwm siv tau hauv qhov xwm txheej no (5).

Cov pov thawj kho mob

Txog niaj hnub no, muaj ob qhov kev sim tseem ceeb rau nonsteroidal MRAs. Lub Finerenone hauv Kev txo qis raum tsis ua hauj lwm thiab kab mob kev loj hlob nyob rau hauv Diabetic raum Kab Mob (FIDELIO-DKD) sim soj ntsuam fifinerenone lub luag hauj lwm nyob rau hauv slowing CKD kev loj hlob thiab txo cov hlab plawv tuag nyob rau hauv cov neeg mob nrog T2DM thiab CKD (n55674) nyob rau hauv lub keeb kwm yav dhau ntawm kev kho mob nrog kev kho mob angioprotectors. (ACE) inhibitor lossis angiotensin receptor blocker (ARB). Cov neeg koom nrog qhov nruab nrab (SD) eGFR ntawm 44.3 (12.6) ml / min ib 1.73 m2 thiab qhov nruab nrab (interquartile range) cov zis albumin-creatine piv ntawm 852 (446-1634) mg / g. Muaj 18% txo qis hauv cov kab mob hauv lub raum thawj zaug ($ 40%txo eGFR, raum tsis ua haujlwm, los yog kev tuag ntawmlub raum ua rau). Tsis tas li ntawd, muaj qhov txo qis ntawm 14% hauv qhov txiaj ntsig CV thib ob (tuag los ntawmCV vim, nonfatal myocardial infarction, nonfatal stroke, lossis tsev kho mob rau lub plawv tsis ua hauj lwm) (6).

Daim duab 1.|Schematic ntawm tus kab mob nephron nrog cov qauv kev hloov pauv cuam tshuam nrogntshav qab zib. Kev khi ntawm finerenone rau cov mineralocorticoid receptor cuam tshuam qhov kev hloov pauv ntawm proinflammatory thiab profibrotic yam. ROS, reactive oxygen hom; CTGF, connective cov ntaub so ntswg loj hlob yam; PAI-1, plasminogen activator inhibitor 1; MMP-2, matrix metalloproteinase 2.

Kev ua tau zoo thiab kev nyab xeeb ntawm Finerenone hauv Kev Kawm nrogHom 2 Ntshav Qab ZibMellitus thiab Clinical Diagnosis ntawmMob ntshav qab zib raum(FIGARO-DKD) sim (n57352) soj ntsuam tib CV cov txiaj ntsig zoo ib yam li hauv FIDELIO-DKD raws li qhov tshwm sim thawj zaug thiab cov kab mob raum tshwm sim raws li qhov tshwm sim tseem ceeb hauv cov neeg mob T2DM thiab tsis tshua muaj CKD hnyav nrog qhov txhais tau tias (SD) eGFR 67.8 ( 21.7) ml / min rau 1.73 m2 thiab nruab nrab (IQR) cov zis albumin-creatine piv 308 (108-740) mg / g. Muaj 13% txo qis hauv thawj CV qhov tshwm sim hauv pawg fifinerenone piv nrog cov placebo. Txawm hais tias muaj kev txo qis hauv covmob raum theem nrabCov txiaj ntsig hauv pawg finerenone, nws tsis ncav cuag qhov tseem ceeb (7).

Txhawm rau tshuaj xyuas kev nyab xeeb thiab kev ua haujlwm ntawm finerenone hauv cov tib neeg nrog T2DM thoob plaws ntau yam ntawm CKD, kev tshuaj xyuas ua ntej ntawm kev sib koom ua ke FIDELIO-FIGARO kev sim hu ua FIDELITY tau ua. Rau cov pej xeem sib sau ua ke no (n513,026) nrog kev soj ntsuam nruab nrab ntawm 3 xyoos, muaj 14% txo qis hauv CV cov txiaj ntsig thiab 23% txo qis hauv cov kab mob raum sib xyaw (lub sijhawm rau lub raum tsis ua haujlwm, $ 57% txhawb nqa. poob hauv eGFR, lossis mob raum tuag) (8). Raws li qhov tshwm sim ntawm cov kev sim tshuaj no, finerenone tau txais kev pom zoo los ntawm US Food and Drug Administration rau kev txo qis kev loj hlob ntawm CKD, CV txheej xwm, thiab lub plawv tsis ua hauj lwm hauv tsev kho mob hauv cov neeg mob CKD vim T2DM.

Tus qauv kev saib xyuas rau DKD yog ACE inhibitor lossis ARB thiab SGLT2 inhibitor. Raws li cov ntaub ntawv pov thawj muaj, fifinerenone tuaj yeem suav tias yog qhov kev xaiv zoo tshaj plaws rau cov neeg mob DKD uas tsis tuaj yeem noj SGLT2 inhibitor, lossis rau cov neeg uas pheej pheej nce albuminuria txawm tias kho nrog tus qauv kev saib xyuas. Qhov koob tshuaj thiab titration ntawm finerenone nyob ntawm ob qho tib si eGFR thiab cov poov tshuaj hauv ntshav. Qhov koob tshuaj tag nrho ntawm fifinerenone yog 20-mg txhua hnub. Cov neeg uas muaj eGFR 25–60 ml / min rau 1.73 m2 lossis ntshav ntshav 4.8–5 mEq / L, raug pom zoo kom noj cov tshuaj qis dua ntawm 10 mg txhua hnub, raws li US Food and Drug Administration daim ntawv lo (Table 1).

Hyperkalemia Risk

Ib qho kev pheej hmoo loj ntawm MRAs yog hyperkalemia, thiab kev pheej hmoo ntawm hyperkalemia tau pom nyob rau hauv pawg finerenone hauv FIDELIO-FIGARO. Zuag qhia tag nrho, qhov kev pheej hmoo ntawm hyperkalemia zoo li qis dua nrog cov nonsteroidal MRA piv nrog steroidal MRAs. Hauv cov qauv nas ntawm CKD, qhov kev pheej hmoo ntawm hyperkalemia tau qis dua nrog cov nonsteroidal MRA PF-03882845 piv rau eplerenone (5). Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) yog theem 2 ntawm kev soj ntsuam kev nyab xeeb ntawm finer enone (BAY 94-8862), piv nrog spironolactone hauv cov neeg mob plawv tsis ua hauj lwm nrog txo ejection feem, thiab me me los yog nruab nrab CKD. Finerenone tau cuam tshuam nrog qhov qis dua qhov nce hauv cov ntshav cov ntshav hauv cov ntshav piv nrog spironolactone (9). Txawm hais tias qhov siab tshaj plaws niaj hnub koob tshuaj ntawm finerenone nyob rau hauv ARTS yog 10 mg piv nrog 20 mg nyob rau hauv FIDELIO-FIGARO, tus qauv preclinical ntawm CKD (5) thiab cov ntaub ntawv los ntawm ARTS yog txhawb kom muaj kev pheej hmoo ntawm hyperkalemia nrog fifinerenone piv nrog steroidal MRAs. Ntxiv mus, qhov kev pheej hmoo ntawm hyperkalemia los ntawm MRA yuav txo tau los ntawm SGLT{11}} inhibition. Los ntawm kev ua kom cov zis tso rau hauv lub cortical txuas tubule, SGLT{12}} inhibitors tuaj yeem txhawb nqa cov poov tshuaj tso tawm (10). Interestingly, cov poov tshuaj loj loj uas tso tawm cov poov tshuaj tau qhib los ntawm kev siv cov tshuaj tso zis los ntawm cov hlwb sib txuas, tsis tas yuav tsum muaj kev sib pauv rau sodium, txawm hais tias kev nce mus sij hawm ntev hauv cov zis tuaj yeem ua rau lub epithelial sodium channel thiab txhawb nqa sodium reuptake hauv cov neeg nyob sib ze. , thiab yog li no, pab tswj kev sib npaug ntawm electrochemical hauv cov filtrate (11). Tseeb, tsis ntev los no post hoc tsom xam los ntawm CREDENCE pom tias canagliflozin piv nrog cov placebo txo ​​qhov kev pheej hmoo ntawm hyperkalemia los ntawm kwv yees li 20% hauv cov neeg koom nrog DKD (12). Lwm qhov kev soj ntsuam tom qab los ntawm FIDELIO-DKD tau pom tias qhov kev pheej hmoo ntawm hyperkalemia raug txo los ntawm ntau dua ib nrab ntawm cov neeg siv SGLT{19}} inhibitor (13). Txawm li cas los xij, ua tib zoo saib xyuas cov ntshav poov tshuaj, nrog rau kev hloov kho koob tshuaj lossis kev kho mob cuam tshuam raws li qhov xav tau, yuav tsum tau ua rau cov neeg mob CKD kho nrog fifinerenone (Table 1).

Cov teebmeem ntawm BP

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov cov tshuaj tiv thaiv kab mob thiab tshuaj tiv thaiv kab mob ntawm nonsteroidal MRA feem ntau ywj siab ntawm BP txo qis. Hauv FIDELIO-FIGARO, cov teebmeem ntawm fifinerenone ntawm BP yog nominal (6,7). Hauv ARTS, spironolactone txo systolic BP, qhov BP tsis txawv ntawm cov placebo thiab fifinerenone (9). Tsawg BP txo qis nrog fifinerenone tau raug ntaus nqi rau nws lub neej luv luv thiab txo cov nyhuv ntawm natriuresis (7). Yog li ntawd, cov steroidal mineralocorticoid antagonists muaj zog BP-txo cov teebmeem uas ua rau cov neeg ua haujlwm nyiam rau kev kho mob ntshav siab.

Cov lus qhia yav tom ntej

Nrog SGLT-2 inhibitors thiab ffinerenone tau txais kev pom zoo rau kev kho mob ntawm DKD, tam sim no peb muaj cov kev kho tshiab los kho lub raum noj qab haus huv. ACE inhibitors thiab ARBs, SGLT-2 inhibitors, thiab fininerenone ua haujlwm los ntawm cov txheej txheem ntxiv los tiv thaiv lub raum thiab lub plawv. Kev tshawb fawb yav tom ntej yuav qhia meej tias cov kev kho mob no tuaj yeem siv ua ke thiab ua tus kheej rau cov neeg mob li cas. Peb pom lub neej yav tom ntej ntawm kev saib xyuas raum hloov los ntawm kev kho mob raum mob siab heev thiab lub raum tsis ua haujlwm los txhawb lub raum kev noj qab haus huv thiab kev tiv thaiv kab mob. Tam sim no peb muaj kev loj hlob armamentarium ntawm kev nyab xeeb thiab kev kho mob zoo, thiab nws yog ib qho tseem ceeb rau kev tsom mus rau lawv cov kev tshaj tawm thiab kev siv rau ntau lab tus tib neeg thoob ntiaj teb nrog DKD uas tuaj yeem tau txais txiaj ntsig los ntawm lawv.

Qhia tawm

K. Tuttle qhia txog kev ua haujlwm tam sim no nrog Providence Health Care thiab University of Washington; cov ntawv tshaj tawm muaj kev pom zoo nrog AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, thiab Novo Nordisk; ceeb toom tau txais kev tshawb fawb nyiaj txiag los ntawm Bayer thiab Goldfinch Bio; tsab ntawv ceeb toom tau txais honoraria los ntawm Bayer, Gilead, thiab Goldfinch Bio; thiab tshaj tawm tias yog ib tus kws pab tswv yim lossis tus tswv cuab ntawm CJASN, Raum Health Initiative, Lancet Diabetes Endocrinology, National Institute of Diabetes and Digestive and Kidney Disease, thiab Nature Reviews Nephrology. Tus sau ntxiv tsis muaj dab tsi los qhia.

Cov ntaub ntawv

1. Alicic RZ, Rooney MT, Tuttle KR: Mob raum mob ntshav qab zib: Cov nyom, kev nce qib, thiab muaj peev xwm. Clin J Am Soc Nephrol 12: 2032–2045, 2017 https://doi.org/10.2215/CJN.11491116

2. Thomas B: Lub nra thoob ntiaj teb ntawm cov kab mob ntshav qab zib hauv lub raum: Lub sijhawm sib txawv thiab kev sib txawv ntawm poj niam txiv neej. Curr Diab Rep 19: 18, 2019 https://doi.org/10.1007/s11892-019-1133-6 3. Bauersachs J, Jaisser F, Toto R: Mineralocorticoid receptor activation thiab mineralocorticoid receptor antagonist kho mob plawv thiab raum kab mob. Ntshav siab 65: 257–263, 2015 https://doi.org/10.1161/HYPERTENSIONAHA.114.{14}}. Grune J, Beyhoff N, Smeir E, Chudek R, Blumrich A, Ban Z, Brix S, Betz IR, Schupp M, Foryst-Ludwig A, Klopfleisch R, Stawowy P, Houtman R, Kolkhof P, Kintscher U: Selective mineralocorticoid receptor cofactor modulation ua molecular hauv paus rau fifinerenone's antifibrotic kev ua si. Ntshav siab 71: 599– 608, 2018 https://doi.org/10.1161/HYPERTENSIONAHA.117. 10360 5. Agarwal R, Kolkhof P, Bakris G, Bauersachs J, Haller H, Wada T, Zannad F: Steroidal thiab non-steroidal mineralocorticoid receptor antagonists hauv cardiorenal tshuaj. Eur Heart J 42: 152–161, 2021 https://doi.org/10.1093/eurheartj/ehaa736 6. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Cov Kws Tshawb Fawb: Cov txiaj ntsig ntawm fifinerenone ntawm cov kab mob raum ntev tshwm sim hauv hom 2 mob ntshav qab zib. N Engl J Med 383: 2219–2229, 2020 https://doi.org/10.1056/NEJMoa2025845

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