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    Cinicl Medicine (imps) Review Therapeutic Advances in Diabetic Nephropathy Hanny Sawa, George Thomas, Jonathan J Tlletelo , Georges Nakhou, Tasha}. Vacharajan ¥O tnd Ali chai ® ‘ein Cr Cin Clon Ov 9S OSA SAAT} tne Abstract: Dike kidney cae (DKD) the met common ase of n-stge Kidney dense {FSKD) in th United Sates Rk atc moat, ich igh conto of nga, a mento hyperensn a! Rypelpdemt an he ne of eninge aero =m (RAAS) toca have teen proven top delay the progres of DKD. fe cet yest eh eapetis icding od cs trnsporpokin 2 SL} nding gon ks pepe (GLE) agent and inert meptor anagont (RA), ave Proviedadtnal uetment opon or pieswith DED. The ee deans the aru Keywords: ats nephropathy dstetc Kdney di therpes SGLT2: MRA pis ne Ten Diabetesis the lading cause of chronic kidney disease (CKD) and end stage kidney ‘hansen, dea ESKD) in the United states and worldwide [21 “Thum. tepn ewes The reniangckrsialdstrane syst (RAS) lacks, with angoensi-converting ramp rn es nay inhibitors (ACE: ad angiotensin expr Blockers (ARB), was the sole ent E2117 htm! option for diabetic kidney disease (DKD} for about 20 year. Ths review discusses the ‘Sapper rent landscape teament option for DKD including an RAAS blockade wth A esi tine mtn OFARD, and newer therapies sichascdiume glucose anspor protein 2(SCLT2) inhbiors endothelin anlagonists glucagon-like pepige-t(GLP-1) agonists, and minealocortiold A er 24 ‘Reepor antagonists (MIRA), along eth summary of landmark ral tht suppor the we ‘copie! the agent Figure) i a 1,37 apo 0550 aT "peacoat | Mo 18 2 Renin Angiotensin Aldosterone System (RAAS) Blockade (ACE-Land ARB) 22. Itaducton ‘The ein-angiotesi aldosterone tte strongly Kink with Kidney ad candi slszase- The angitersin converting enzyme (ACE) canes anon To angers ‘which has pro-inflammatory and pro-bvotc eet), ncteased sympathetic act, {resed tale sodium and clo absorption, sneesedaldestrone een terol ‘vasoconstriction and ADIT secretion. ACE alo plays. fle in bradykinin metabolism] (Figure gure 2 Vil presentation ofthe enn-angotesin-akksterone tr (RAS) an he ech: anism of scion of sngotein converting ensyme ton (ACE) an angiotensin reer Noches ACE inhibition and the angiotensin blockade inthe form of ACE inhibitors and angiotensin receptor blockers have been proven tobe useful in paints with Kidney and Candie dace. The tects of angitenin on key autorgulton was described ey 185 [5], Over the following decade severl sues showed decreed albuminuria [6] tl reno protective eet withthe RAAS Blockade (10), ‘ACE sand ARBs have ben ell describe in the tert, with landmark ta proving the therapeutic uly of tislass a drugs foe paints with DKD, and remain the ‘aisty of management of DKD (Table) | Mo 18 36 capopi i] Publication Yor Tesiments), inary Compo Rik Rotction ‘Doubling ofthe basin 0 pope po Ena a 2001 losin plato, Datingserum 6s " 37 08 ‘medication induce bypeskalem [5 2. SGLT2 Inhibitors Bs. Intaducton Intl studies with SGLT2 inhibitors explored thar wy in improving blood sugar conta inpatients with type Il sets mets (T2DM) by virtue sees urinary loose exertion [16,171 “The beneficial eet of ths class of medications are now knowa to go beyond their fuconuric elec, wth independent canliorscule and ideey benefit lorena hyper ci es. 178 tension sone of he maladaptive mechanisms ofthe pathogenesis of DKD. The impact of SLT? inhibitors on this proces romain the moet daly acepted mechanism resign ‘idney protection By backing SGLT2 inthe ronal bul, SGLT2 inhborsprodce 3 ratsuretic tet, which induces tabulo- glomerular leeack reli in anocotition In theafeen arteriole reducing shomeruarhypetivaton [3 The reduction in hyper. tation, as with RAAS ihitors,lumately sows the progression of DKD (Fgute 3) {SCLT)inhbors Top Under nna censans sem ad coe tbh Rabe "yy SGLI2 to ter he pou tubulr ce. The soi he ett the stra se the oval consul ule PCT though heodiun-potshm exchanger, while ace ita [GLUT2 tout he PCT el. The presets of xe ano he bata de of he PCT ce cam and gent nest peg, sling hn dee exe mas | Mo 18 proton an ios Mlk Back SLT2 ls inincened iam chose dey "emors dal potions of he nephron. Thi increased human end nse Byte maa This vasoconstriction wil decrease glomeruli lean at gomerulaehypertesion. Botan: SGLI? intr licen the production of plea tne bodies, The matics by SGU initsto wl dene he xeon fhe plea toe bein the rine Thee het edo ar prfrenallyoidie oer ty ade which ply aan dora ate Aside from thei fet on glomerular pressure, has also bow hypothesized that acevo icose uptake in the tubules can potentially contrite to proximal tubule production of extracellular mats proteins, wich may slow the progression of CKD [5} [nadaition stadies have shoven tht SCLT2 inhibtors can sme ationidant and a8 inlammatry signaling pathy OL which an potentially reverse molecular processes related toinlammaton extracel matrix turner and resis [21. ‘Another hypothe that SGLT2 ihr can induce low ketotc state though the incrosed proton of ketone bois and thei decrease urinary excretion Tis thrifty "state" thaory hypothesis Ut the evel of ketones cn be peeerenally oxidized over fre fatty acid which play 3 rle in the dereased oxidative sees on the Kidneys nd hear [2.25 Numerous tral have now established the cardiovascular and kidney benefits of SGLT2 into and soled thei role inthe management of patient with DKD ad, ‘most een, proteinurc CKD in general (Table 2. oe a. 1,958 Pat es YearPubinhed “Teatment 6) ‘Composite Kidney Outcome rand Ratio 95% CD EMPAREG OUTCOME EH 205 Empopiorine poate Scondany Shey epic hry deh on ostquoa7s) canvas) 27 Canaglitainys peso Seconda cy placement therapy or deh on nscoraz7 End ag cy dene, doubling ofthe ‘CREDENCE Ps} a9 aati, plsbo Panay sinensis or 07005905 DecLARE-TDM7 29 Dapagicinns plssbo Seconda redaction in eFR ehonie EMPEROR Ros 2) mn) ——Empupionn poate Sxondany “Sins eal ann ors asves.07 GTR 1-15 n/m nde Maney de, ssid ston era KIDNEY met Empapionin ve pao Prmaty seca} 7m a dah ning ARNIS sh decrease ineGFR to =A mL/min/ 173m ESKD or dst rom kidney or cndhowsecla cae. The Raza ato forthe vena compote was 176 (95% CL O67-087), The HR with incisal components of eal comport improve even farther t (53 (5% C1043-056) [27 “The Dspogiforin in Patients wth Chronic Kidney Disease (DAPA-CKD) transom: tae patients with an GFR of 25-75 mL /min/L73 mad a UACR of 200-500 5/8 10 ‘Reite dopaplilain or placebo, and wa designed Wo nvetgate the long tema a ‘Sfety profile of dapagorin inpatients ith CKD, witha without T2OM. The primary futcome in his el was a compesite of a sustained decline i the GFR ofa ast 0», ESKD, or death om kidney cr cardiovascular cane. this ial nly 67 of the patent had DM, and heal showed a ignfcaly Tower ck for the primary outcome in patients ‘ith CKD, irespective of whether they had DM. The primary composite outcome had Sn HR of 161 65% C1051-072) [25]. Sky results were consistent across prespecified nalyssf partipants stratified by diabetes stats, GFR eutot of 43 mL/min 173m, tnd UACR OT ge The EMPAHG OUTCOME tral compared empagiflorin to placebo in pints wth type 2 diabetes and a high rik or erciovacculr events, an had a primary compesit futcome of dah frm CV cues, nonatal MI oe nonata toke [2 Ina separate report ‘viewing the key outcomes ofthis tral the ate of doubling of serum eestinin eve Accompanied by an GFR <1 mL/nin/1.73 ination of kidney replacement therapy, te death rom zenl cause wos found tobe ower with empaghaan (HIE 04; 95°. CL 040-075) (50 The EMPEROR-Redued tra assigned patents with lasses T-1V fet aur to receive empagflin oe placebo. Compote renal outcome was one ofthe secondary ‘utcomen, snd this was defined asthe need for chronic alysis or Kidney tanaplant, fora 40% daceace in eGFR, ora sstaned GFR 15 mi /min/L73 me (i baseline GFR was 230 ml/min / 173 m2), oe 10 mL/min/ 173 m2 i te baseline «GFR was EM mi min/ 173m) Paints with an GFR 20 ra /min/ 173? 38 hee of and laaion were excluded from the Wal. The composite Kidney outeomne had an HR of 030, (osecrns2-077 1) “The EMA-KIDNEY tril ian ongoing stay with empaglirin for patents with (CKD for atleast 3 months prio sctening, which was defined as an eGFR 20 0 | Mo 18 <5 mi /min/ 173 of boy surace are a GER >45t <0 m/min 1.73? ith 'UACR 2200 mg/g. The primary ostsome ra compost of FSKD,sstned retin GFE to <1 bmn /1.73 me Ldney death or asstaned decline of > 4% in eGER rom ‘andomizaton. The wecondary outcomes inthis sty incase CV death, hospitalizations, tnd alkcause mortality 1, 23, Prt Considertions With he apy increasing utes of SLT? iio, here ae numerous things 0 ecpin mind “The incess rate of genital infection cased by SGLT2 inhibitors can be adresse by education on hygiene. Pes-ares cleaning after urination a before sleeping can belp ftcrenne the kof genital infctions aed Ute Patiets should ala be este to eck hop i they experience genital icing ‘Given the diueticeffect of SCLIB inhibitors, a sick day proto” canbe inperented where the medication f held while a patent sl, espeily if they are expenencing Symptoms suchas nausea, vomiting of diathea. If patient i aleody ona elute, ‘lecreasing the done ofthe diuretic ca alo be considera at the te of SCL inhibitor inition fo decease the chance of wohume depiction, ‘Although SGLT2 inhibitors donot cause hypoglycemia, they can end tohypogycemia when he ptint ison another agent such as insulin ora sulfonylurea thereto, dere ing the doses of inslin anor sulfoslurea could be appropriate when ading SGUT2 Inbitors nally piven the increased sk of diabetic ketoacidosis (DKA), these medications shoul be approached with caution inpatients withastory of DKA. When the mediation [estar patients shouldbe educaled for the eaelyrecogation ofthis proces, A. GLPA Agonists {Eh Itodution Guage like peptide 1 ar ncein hormones secreted from cells inthe ower gu in response to food intake ae an ineresse in plasma glucose. These inert horas faclitate insulin seration from pancreatic B sk clls suppress glucagon section, day atric prying and induce ebing of satiety [23 Tn aciion fo the pancreas, GLP-1 receptor ae found ina vant of ergans,ncuding uta lite othe ung, toma and Bade [135 ‘GUI has also shown to have names ney protective tes incading the inhi bition ofthe inammatory fects of angiotensin [sad the inkbion of xiatve tes 2 albuminuria [37] a wells anally to ameliorate buminusa,glomerule hyper tration, glomerular hyperophy and mesangial mates expansion nana! mols [35], (gure). “he ial ws of GLP-1agonisn was supplemental agent o ait wih the conta ‘€T2DM and iteas oe used axa adjunct tether agents Is weight los properties prided an additonal bene, But recent als Rave further demonstrated cahowssular sd Kidney benefits, making ths medication anew potential option or eater wliaation in patents with DKD Table oe a. 1,958 Tal YeorPobliaked TFeamment is)“ imaryor Ss Kidney Ono Resa LEADER) ae rate vs plssbo Seondany Disbei Nephpsty HRI CLONz-05H) ‘ican, doubling of ram SUSTAINS [0 ane Swnagadevs plato Seandary coating Coin Saran = Smt aia ROG QS C1A6-A) ‘cine in GFR othe ulate nstn waRD2 ans Ssondary Gand UACR nein arm butt be ‘oe here gti ar 300 mg/ > UACRIn lower aslne ewIND I ans Dulles. paso Swondary conuinton ssanad SPS >eGFR ROS 8% CLO77-059) Sg nese TRUACR of tft 9% fo sn, AMPLITUDE [4 am peptide ve plasbo Sanday atncGhh decane We lors Aldays, — HROAS I CLOS7-07%) Ter yeeros, eGR <1 forays Tera > Si rducton a sGFR, aching ow “Tobe completed inh Sagi vs plsrbo Pramary SKD deh fom ey seo eth a Ongoing "RROD = onc ra alo Ae Wp aes ARDY = Sagse vcs ln ing a ops ead lente tomr ei Haney duc Ci cent al CRAY = snes repent erp C= ans UW = age ea eben ppnow emt eal nse isnt ith pe iss ey Sac eS ar oar ia a RD eg aly PHEADE= apadee and st ncaa oe be REWIND ae ‘eons terse ones STAN evn masiron seinem ome wh soc mneno pee | Mo 18 Figure 4 Vil representa the mechani of action of gage ike pp 1 (GLP) a welas GLP agenistsond dipeptidy pepased (DOP ors" Theanamnatry c. asennad nthe ea and dn 42, Landa Tri “The initial tris for GLP-1 agonists evaluate candiovasculr eet, with sect studies examining kidney proective eft. “The LEADER tril was an carly study investigating GLP-1 outcomes that proved insights into potential Key benoit. This tl randomized ptints with T2DM and Ig CV rik in recevinglragltieo plac. Roughly 75% of tse patie’ had sn eGFR > 60 ml./min/ me The primary outcome in his al eas the endow nc tutcome. Secondary microvascular events evaluating nephropathy was lower In the leagltide am (HR 0.78 95% CL.67-082). This tal also showed that Ue roup With GFF 30-59 ml /min/m= had an HR forthe primary ec point of 7% C1OSH-AS, ‘whereas those with eGFR < 30 mL/min/m? and cE > 60 mlL/min/m? did not have 2 sistiallysgnlicanciference nthe primary end-point, when compared with the plato [1 “The SUSTAIN-« tril compared semaghtce o placebo in ptints with TDM. The primary outcome in thi study was CV death, nonfatal Ml, or nonfatal stroke, One Df the scondary otcome=-—"new or sonsening nephropathy”—inlded acres ‘rinura, persistent doubling ofthe serum creatinine, creatinine clearance fess than {m/min or the ned lor ily and as lower in te semagltde group (HR Ut S570C46-08) [0 ‘The first major randomized tral involving GLP-L agonists that pecially evaluated patient with meerstoforsevere CKD was the AWARD? tial A number of 4 CKD [atients were randomized II to either recive dag 38075 mg weekly o LS mg ‘Weekly, ot receive insulin glavgne as basal therapy. Secondary outcomes inluded ‘hangin GFR calculated with the Chronic Kidney Disease Epidemiology Collaboration {(CKD-EPD equation by cytatinC ad serum creatinine) and UACR, There wasa significant sdocrease inthe UACR with the igh dso (8 mg) dul arm, when compared with the placebo The tal aloo showed tht the nsulin arm enperiece atta sige ocraze in GER at 24 wook, whereas the two claglutide arms kept eGFR sir to ‘shore wast the str of the tal [I “The REWIND tal was designed oases high-sisk condiovagculae patients with | trond rangoof glycemic control witha weakly subeutanoous dee of dulglutide versus | Mo 18 placebo The majority of thew patents had an GER of >0 L/min. Kidney dine ‘was one ofthe secondary outcomes inestgated in histidine as the devetopment fafa UACK > 30 g/t those wit lower baseline concentrations sustained 3% 083 [paler devine in eH or chic ne for KR. howe randomized tothe placebo arm Fad 407 kidney ineidems per 100 person-years, compared with 347 Kidney incidents per 100 person-years for has ee late (HR O85, 95% C1 07-083) (2) "A metoranalyis with a oa of 56M participants from seven tril ncacing the LEADER [5], SUSTAIN [0], and REWIND [1 was nado tothe ELIXA [1 EXSCEL [16] Harmony Outcomes [2] and the PIONEER 6 [5] wal, showed a 17% corse nthe composite eal cutee ith GLP-1 agonists with an IR of O83 (5% CI of 078-08) [3 “The AMPLITUDE.O tial compan efpeenaid to placebo in pans witha istry ‘fC disease of CKD, defined aan eGHI 9250-599 /min/ 1.732. The ial ide ' composite kidney outcome, which was defined as inedent mirotbuminuria with 3 UUACK of 500 mg/g > UAC at hosel decrease in eC > 40% foe 30 days oF ‘mors, KET > lays or GFR 15 m/min 173 for 230 days. The composite kidney futcome inthis wa eccueed in 13% of those ecelngefpepienatie, versus 1.40 those rcv placebo (HR Os; 95% C1087-029) [3 “The FLOW tal san ongoing, DKD outcomes tral with semagltige, where the Pima end-point isa persistent 30% or more reduction i eGFR, an cGFR of ess than [5m /uin/1 73: iihation of KRT oe deat rom kidney disease and death fom CV case 42, Prt Consirtions Given the requeny of gastrointestinal complications related to GLP agonists such ss nausea, vomiting and dlartea, is important tart these medeatons tower des ‘nd rate slowly. The prescriber shou 0 make sre ptient ing stares m3 GLP aonist aware these elec as tolerabiites ae being determine. Fuetermore st may be necessary to adjust oer diabeti sgents when a GLP-1 agonists bung initia fo ‘voi hypoglycemia. GLP-1 agonist should not he used in combination with dipeptiy peptidases (DDP-4) inhibitors 5. Mineralocortioid Receptor Antagonists Minerlocrticod receptor (MR) mechanisms af ston excel eyond ther antago> nism on the epic sou channels ENAC) in the olin tubules Mare expressed linumerous sues including colonic, cardiac and vascular sues [5]. In addon to Aid and fn transport MR sso play an important rl nthe adaptive response jury [1 Activation of these receptors has been shown fo incense ective oxen sPeCes 2d inlammation [2], and overexpression a this eeptr as bee shove 4 a eal hypertrophy [5 The erber minealecoricol receptor antagonists that are sil widely used are spitono- laeone and eplerenane These stridal MRAs were shown to proc fom oxidative tes inanimal meses [5455] and nadtion ting fective antihypertensive ages, lan ‘mark tals sucha the RALES [5] and Emphasis HF trl [57 proved thir Benefit and ‘sly i pts with bear le Subsequent mets-anlpses showed that these steroidal [MRA ar efective agents eucing proteinuria in ptintlready eated with an KAAS. blockade (5355) Despite this potential real bene hese dug remain uncertiized in patent with CKD, given the concer for byperbalemia [8] and worsening GFR 6 “The itrouton of om sterodal MRA, th he mast notable ing een, aM ‘with great promise for potently providing cardiac and protenure beets, while having 2 lens profound fet on inducing hyperkalemia. Finerenone as sumer proper: erent fom the steroid MRA, ining its tissue distribution anc the mode ‘which i causes MIC inatation, as well as oer pharmacodynamic properties) | Mo 18 ARTS 2) ARTS ON) IDELIO.DKD FICARO-OKDIES Finerenone is welcome addition to ur armamentarum, promising the seen of str MRA, but with es ie efects Numerous landmark tia have recently Been published demonstrating the therapeutic potent of ineenone in DKD (Table) “able Summa dark a th MRA a rrr—~— Fr Song nin m5 7 = _placebo-corrected mean UACR ieto drop mec Kidney aire > 20 drut cc th Primary Ras gexcra7s.099) rome ease zat derestinccF death Sonny HR ns7 eoH.c1076-100) romney cose TRIST Hiri Wespr Arig leap spay, ANSON = Misha Rap ‘etn HBRLD-ORD «erent ene ops ae ‘yas GARG ni mrs ey sy 5:2, Lander Tiss ‘The Minerlocorticoi Receptor Antagonist Tolerability Shy (ARTS) paved he way foe future studies ino finerenone. This study was divided into two pars where part A ves perormed evaluate the safety olerabity and Kidney elf of the dry le Port included patente with moderate CKD. Th stady showed that fnerenone vss st Feastas effective a spronalactone in decreasing biomarkers for hemextyamic tess, while inducing es hypertalemia a decrease real anti [2], ARTS-DN tik the flo Up stuns designe to compe the efcay and safety of varying doses of Sereno 10 placebo inpatients with DKD and albuminurla. The study showed tat there was 3 done dependent decreas in albumin in patents receiving Gnevenone when he dose swaeteen 75 my ae 2 mga dy ‘Bulking onthe ARTS tit, the FIDELIO-DKD tal was a clin oucomes study of finerenone compared to th plac inpatients with T2DM and CKD already treated with maximal dos of ACE-Tor ARB. The primary outcomes inclu key are ened {SS ESKD of an eGFR <15 mL/min/178 me), > 40% decrease fom the baseline GGFR OF ‘eit rom Klee ease. The primary outcome wee sigan ren the finerenems {roup withan HK of O82 (5% C1073-085). Hyperkalemia ocurred in 1.8% patents {nthe inerenone am, compared with 48% of pallent inthe placebo art 64. “the IGARO-DKD went beyond what was investigated in the eaier FIDELIO-DKD tra evaluating patents with T2DM witha boarder ange of CKD stages, Pint inthis study were groupes into GFR 2500 mL /min/ 732 with UACK of 30-00 mg and fneGFR> 60 ml /min/ 7m? and UACR of 30-50 em. The composts outome of ney faite, a decrease ofa east in GFR and dest ftom Kee case wo the secondary outcome in dhs tral The compost kidney outome Was 95% nthe erent roupand 105% ofthe plaeso group with an HR of 57 05% C1 076-101) [5h | Mo 18 SONAR IZ] 53, Pil Considerations ypertlemia remains asides that a preseriber shoul be aware of when stating fiesenane. Other common side ects include hypotension and yponatems 6 Endothelin Antagonists 6. Itraducton Endothelin comprise thee srucurlly sir peptides involved in various vaso- constrictor patsy i The Kidney expresses endothelin receptors [7 and there tsidence of thelr overexpression in diabetes, The rena endthtin system has Bee show, te play an important role sn neal eal faeton, and derangements of this str ae involved inthe ntion snd progression of DD, HTN an even glmerase neh “Endothelin recepor antagonism has been shown to improve Kidney microceul- ion [6], ane here has en evidence that endothelin antagonism can lower urinary protein excretion [0 ‘ven ths evidence of potential kidney benefit, als haveben conducted to assess ‘he benefits oF endothlin antagonists inthe tateent of patents with DKD (Table 3), ‘eS Summa anim i withenha meno es. Tiny aes Tas Tas Dohingefsrum —_Nosigifomtcaagen— Malendalaty decoy costing ESKD, ath prmaryoacome compose comet eid oa Por manera ca SERGE Seca are et a on™ Spcpabietichen Doubling of serum Doubing ri R048 (C198%048-085 62, Landa Teas The ASCEND trial andomized patients to receive either avosentan or plac nd the primary outcome of the tral was sidney comporitewhih ncladed the doubling of serum cestinne, ESKD, or death, The ral was terminated ear due tosafety conns ‘lated to volume overload and congestive heat aur. AMhough the was a statically "igniicen redaconin the UACRin patients the avoxentn ary here wasn sail "Npicant ference inthe kidney composite [71 The SONAR tal was designed t evaluate whether endothelin antagonists could havea roe in certain poptions with DKD. In thistria patents with T2DM, an GFR {925-75 mL/min/173 and » UACR of 200-000 ang/ on msi olerated RAAS boctade fo 4 wesks were iil ested with asntan during the enichment period Pens who tolerated straentan without substantia vlume retention were then on domized wo receive alrasentan or placebo. The primary end-point Wasa kidey composite ‘which included the doubling of ram ewatnine for» 30 day, or ESKD inthe intent fo test popalition, The trl shoes that the patents who oleate the endothelin antagonist hod improved kidney outcomes with HB of 045 (195% 048-028). The ial di show higher amounts of uid retention and anemia inthe atesentan arm. Moreover, higher hospitalization for heat allure wasseen inthe atesentan am v= 26% ine placebo ‘ro although he dference was ot talinically sgt [72 | Mo 18 6, Pil Considerations Given the early termination ofthe ASCEND trl and the “enrichment period” per formed in theSONAR ta tis important to monitor foe sigs of vlume ovetoad should 4 plient be started onan endothalin gon, 1. Rotenil Future Therapeutic Options In adkitin #9 GLP-1 agonints, thre scart evidence suggesting DOP inhibitors could provide benefit for patents with DKD. Tels sch ae SAVOR-TIN 83 [7] an CCARMELINA [4] showed a posible rection in albuminuea in paints rceving, Given the role various inflammatory pathways have Been shown to payin the ro- pssionof DD, pharmacologic intervention argon these patsy have buen asa of Interest or potential tealment approve. One promising pathway involves |AKIFAK2 Inhibition barctinib. Ths hasbeen shown to decrease albuminuria; however itemans ticlarhow it would afc the progression of DED [5], Ober potential ages clad "iflric therapy with pirfenidone or pentoityline (75, Nos /4 inition [77.75 nd chemokine cytokine Inhibition (|. Further investigation and cia was wll, show whether thee innovaive herpeutc interventions willeverualy make ino our ‘expanding repertoire of management options for DKD. The future of DKD management has the potential to include a more personalized ppecach, where each pte an havea taloed tate ogieen based onthe genetic ‘et biomarker profile 1 Summary For years, RAAS inhibition with ACE- and ARBs was the sole therapeutic option we could offer patients with DKD. These agents certaaly remain the eoenerstone for ‘managing thee patents but we ae now fortunate tobe ale tafe ote agent hich an complement the benef the RAAS blockade 'SGLT2ilitore are taking the nephrology world by storm with unequivosl pots tive Benefits that extend beyond DKD GLI agonists ae now prefered orl agents for the managements of diabetes in CKD patients, accoeding othe Inaugural KDICO gule- lines [I5}Fnernone nase avery weleome adion to aur rowing armamentara, 35 we get closer ta guideline directed medal therapy for DED, which wou include an [ACELor ARB, MIRA, SCLT2 inubitors and possibly a GLP-1 agonist. We are fortunate tobe living in an ert where we ae able to fer ntervenon ot oy slaw dws he progesson of DKD, bt also prevent adosascla complications and improve sv ‘These expanded herspentc option ave ushered na new era of DKD management, bling cardiovascule, adn, and survival bone Author Contibatons: rary dat nese of Here HS, AM) Out of ee TH fl AM Eating andl def (AA, TJ. GEHL angGN. All authors ave ead a8 ped othe psd vem othe mana ‘nk dy Da sang not apples he al Acknowiadyment Fg? dap rm “Rei Anglin Syn by Bere on 0) Reeve fom hits /app/bisrenercom vender rps igre and crete ith Pender ont of ttre: Hay Sowa sting tds; Gang Tas: Por EMPA Kin Sty Jer abe e-PIrEMPA Kidney Stay, for SONAR stay an Royals or AatraZoncs {Gg itt ting dae Tar aos ng hs AMEN Rae ci es. 178 tae Areva ACE _anglotnin convrting enzyme lahioe CCHF Congestive hart a CCKET Gone idee eploement herspy Ch Soden ner DRA. dnbet ht acdoss RD. dabet Kune dese ck ENSC pl sadurehone {GLP glean ie peptide Ser IY pms MR ibrar wept NRA. ferlecotsd eopr antagonist BAAS _reninangisesi-aldestrone soem ROM pelle elit UNCR tie abumin etn to References 1. Une States Renal Dat Sytem ISDS 2016 A Dae Rg: Af Chron Kine Di on Et St Rea isin i neat Nationa Ia of Heth, Nato lta of Obes and Digestive ad Key Ds: Beth MD, 2 Inrtnal ibe Fesrton DF Dia as nemotonsl Det Federation: Brass, gu, 27 ‘Amex MK; Atkins CEP The eiangitrtraldasterone ster and supra Ml, 28,33, 3-88 [Cronles} 44 Monta Vi Clea M. ACE nbc anges nara 209,78; 1. [Cross] 3) ythe Wi Cappel antares, Enh I Mo 196,95, 200-0, [os (oh {Home E; Pari ILI; Mabise Edson, 8 Danke Nien, t; Cia, of aptopl n ieey fncton a Sulnsepennt tc ats wh ephrpey Br el] 1986 23, 467-40 (Crosse 7. Work Spey, Gs Me, Hs Gran Gs Here HL: Aurel M Benes fates converting eneyne ‘this on real anton in pants wth abet raphy: Be Mae 283, 21-74 rl Panes | Lage C Rater, Laure, Anipteinae et of aptopelin pinay ghomeralrticine Naito 17,45, 99-100, (oat) 9. Tha: Naayrm, Doms Shari Yarazah Yar, M, Captor a angen one nzy ne ini, ‘ces peta n hypertensive pth eal anes Nop 19%, 927 forest ono] 10. Hage ng Psa dr Hem, Ks de Zavaro by anton emerge neon ine 147327688 ott 11, Lewis El: Huns Lm AP Rohde, RD. The ec of Angiotensin Converting zyme Inhibition om Dsbte pip: A Eng TM tm, 29156196 (resell) 12 Setar BM; Cooper MIs de Zeca Ds Keane IF ite, WE Paving, HL; Remus Sapin, SM: Zhang ‘Shinar tal ets of aan on eal and cards otses patent th type? abet na repost. Eg Mal 201,35 -, foset 1, Lavy Humic, LG Cake, WR He, Ts Po MA: Lao, is Riz Akin RC; Rak Re Rap Le al enaprocive tof the amgntensi-eceplo anngoni bata patents wih peppy de ype 2 dees Eg Ma 201, 35 Sa, essa Pas 14 YS To, Ks Pog J Dya Ls Colin Schumach Dagens Slight Ps Anderson C-Telnstn mip run pt aig fk for asco events Nl 2, 386 154-19, [sel Pe) 1S. dodo Lf Carman ML; Chan JON Heep HL: Hat C: Kins Ks Lit A; Micha, ED: Navanoctian, SD, ‘Gm, WA etal. Easting say othe 399 KICO Dil Manageent in CKD Guline Evenoc ned ove ‘smog ad teten Kiyo. 28, 58, S888 [rose ci es. 178 et 16 Shs.$: Devin Ds Chon, A Plot D; Chen, S; Wen, D; Sly, Ks Demarest K Rahaman 2 ‘novel inher of sum ase coransprer 2 dase depen ees ule rel hel frac nce nines ay slucue extn nly subj Dies Cer Meh. 291,13, 89-472 forse [PN] 17, Davin Bz Moro L; Hemp MS Vanbch As up] Nape, Ks Shar, Canon inprvse _ewmic contol over 5 cy nsec wih ype 2 db ot pinay carl on lin Dien Cb. Mat 221 So0.3 (cries) 1, Fonts Zamlon Asst, Mi; Bose Ls tor SGLT nbtors andthe Diabetic Key Dies ie 216,39, SlasS71. [Cnn] 19, Girt Sali ace kd trareporte ins tl rept yon ld lane ing? Kay Ir am 5, 083-70 foro) 20, HH Lasker Han A Zin Za MPa, Rabon MAM; Khan Shan Ni Alam, MA Canalo ‘dative sess model ey. 204 10 145 fest) 2, espn Des Mine MBs Ds Menger. Pars Canali Sows roreson Renal uncon ‘Ds depen of yer cs Am. ee. O28, eae 2, Feral Fs Mark, Mz Mayou ECV Potton nthe EMPA REG OUTCOME Tra A “Thy Subtate” Hypoteas ‘ees Ce 39, 18-118. rel 23. Moats; Allo: en Ri Can Sit in Furl Ese: pin he Reel Crores Outcomes inthe EMPA-REG [OUTCOME Study? A Untying HypthesieDves Cae a6 3116-1122 fers Pons) 24 Zinman, B: Wanner C:Lachin, IM: Fiche, Ds lm Hantl Mathews M Devin Thane, OF: Woe, {ies Epon. Carraeulr Outcomes, nd Maralyn Type? Dabo N. Eg Mt a8 373, 2117 3138 {reste Pabst [Nel Feri Vs Maha KW: de Zc D Fah, Eon N Shae, WL Desa M Mathews, DR: ta {Carlton ap avast and Real vets Type 2 Dies NB | Me 207 37-87. Cx (Pb ea Pea V dine AA] NeaB: BarpintS: Hew HL Charan DAM: Ear Rz Agua Baki Bl ‘a Canlaon Outs Type2 Daksa Nophpay | Ml 08,360 285-24 cr] Pabst ‘Wit SD Ra mac, MP: Mewenzon 0, Kat ET: Ca, A Sherman MG. Zener TA; Kae LF Marpy SA: ‘1 Dapapliorinand Carvasclar Oates Type2 DittesN. Eg Ma 38 32-957 [ec Tea] 25. Hewspinks HILL: Scion BV; Core-Reter Ry Cher GM; Greene, T: Hou, Fs Mann FE MEA FIV nen; Rosin, Pt Daptiornn Patents wih Chun Kidney Dae Engh [Mel 0, 38, 48-1686 (crest) Pacer M: Ane SD: ti Piipatn G; Poach: Canon Janz: Verma Sat Beaman Metal Canvas an anal Ostcres with pagan Heat Fall NJ Hl 36113-1434 [cre] 50. Wenner © EMPAAEGOUTCOME The Nephreog ein of Vwi Mo 27,13 9-72 [ol 2M. Rhee slain, schon GML Mate, Des tne neon one a ah acne etranpere2 iho Less rn CREDENCE an expetatios fom DAPA-HE DAPA-CKD, ond EMPA-KIDNEY. Die Oe Met 2, 22 4-54 (cee) Tina Tigi, Vs Wd, T:Nagak Mt, The potent for eoprctan whines drugs. Kidey 2, ser700711. erste 58, Tarn, MLDS, Ds Gun, sk S.A: Edwards, CM; Mera, Ks Chol Tals GM: Host MA Lame PD: fal Alef ghcager-tie pepe in thecal ulin eng, Me 196 3796-73, ern] M4 Balok ee ane Tee hon of menenge shone acl ncn the afaik opie tect. Erin 19 17. e620 (roel) 55, Campos. RV Les YC: Drser DI Dvengnt sue spec and developmental expression of meeps er glucagon and [lan ike pepe int mare Endl 199, 13,26 16k ero Pb 3 Mima A: HimataNomomot, JU: Kl, MLC Gevaldes Ps Mosumoto Mz Mizuta K Pak KCail.C ea tse cise of CLP on glomerlrethelu and ta inibion by PRED avai eet Date 016, 27-27%. [Croke ube 57. Henao HInguct, Te Mae, Y: th N; Zheng Tk; Yohomign Mi, E Sona NTehayang R GLE? ‘snl ste protect apie olde re and albumin epnstcin ined abet tin pron Knse ‘Novant ihn of el NADIP ones: Melo a 67, SE 168 Fees [Nt 58, Kodera shat KKotska HU Takata, Miyamoto SS M: Kaftan, N Nei, SSor K: Hint, ‘ol Gicagtke pp receptor agonist aoa eal nary hug ran infimmatory acon wiht eng ‘angen el narat motel ype abet, Das 201 5, 988978 fons] 29. Mana SP Dans CH Brown rane, K: Ket Pann FE: Nbuck, MCA; Nos SE cock 5 Poul, ‘av Sea Lilie and Cadhvaclar Outen Type Dae, NE Mn 216 375, 11-03, Crome] ci es. 178 ae “AL. Mano, Si in SC; Cons A Blache PG; ida Es ety LA: Lingua Rosertack, J Sev, Wien, ML Sa. Seagltide and Canons Ovens ans wih ype 2 Dabs N Engh 1M 2046 95, 1B (eso) 41, Tht Rs Lalshmanan, MC: Rayne Bs Basch RS; Zinman, AG; Woodard BB; Bots FT Dulane vers ‘rsln gine in pti with ype ditt a odeatessevre hry dae AWARDS Ae ‘polar al ant Dats Emit 2008 6 05 a7 for) 42 Contin H.C: Calhoun HA; Dagens GR Dae Labshnnan MPa Pb] Rieeye Riddle, MC ‘yen etal Dll an cad nclr outcmenin ype? deter (REWIND. A doen, random Fao cote al Ln 208,394 128-10 [ket 19. Krotrne Lath nd PS Dechert KF Salt NPD: Kober Pete MIC: MeMaray LV Cantante, ‘iy nina li appr enh dat sya and {4 Cnt IC Sat Horse amasandarhotige Crate, R; Lopes RD; Lam, C0 Khurmi NS. Heenan Ls ‘att Seal Cason and eal Gace with fppensieln Type aes NE) | Me 2, 8, (Creme) 4 lor MA Claggt Day, Re Dit, K Gente, HC: Kober, LV Lawn, EC Png 1. Wel X Les Ft Usboutideia Fens ith Type? Dns at Ae Carnay Sire Ng). Mid 2D 5732872357 cml 46, Van UR Behl MLA: Nant Thompron, VPs Lleyn, Bane [Bhan JC; Ch | Casares, Sl Ns ‘al tts of One Weekly aerate on CadovascuarOucomesinTypea Dae NE Mel DO, 377, 1812 {Crookes Pabst |. Memande, A. Coe, [Bs Janmnohamed 8: D’Agoting, RB: Granger, CB: Jones, NI Li Az Rosenborg, AEs ‘Stpmin EN Serle MCtal bight scl cards once tens wih iype 2 abc and atone lar ‘Asem Harmeny Ota A double ng rndomaed pct coir al Lae 205921519199] 48 Husain, Mz Beeld, AL Dosa M, Dungan, Ke laschentz, FG: rapa, DR: Keppesen, OG Ling Eng [Ma 299, 8, 81-881. [set ‘Willa, DSt Evan BU Seagate: Charting New Hexion GL Analogue Ome Stas, Dish Ther Ro Tn hu ite Relat Dard 2 1, 221-295 [al 50, Bonafipe, ME Bonnar. B; as F Mingakcoriold Receptor ant Cardiovascular Dist, Am. fae 208, 3 MeEIPe (Cros Pte) 51. Com-Saner, Es Comes Scher, CE The muacet mioeraoortcl expr. Compr Ph 201, 4 46-284, (Cesta) 52 GamcrSncher, EP: GomenSucher, CE Contra ulation of bled psu by the minerlocores cpt Met Cal Enda 190, 28820 (ro Pb 53. Leone bar Bias M: Venger S: Muito ML; Water, Zena, MLC: Lambs M, Altern ‘cara nd a fancies in ranapei mice oereprnig human minerals plo | Bi Che. 201,276, Se911-390 [Cros Ped SM. orera

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