Nephrotoxicity Ntawm Immune Checkpoint Inhibitors: Kev Ntsuam Xyuas Tsis Zoo Los Ntawm 2013 txog 2020

NephrotoxicityQee zaus tshwm sim thaum kho nrogImmune checkpoint inhibitors(ICIs). Ob peb txoj kev tshawb fawb sib piv qhov sib txawv ntawm cov tshuaj no. Txoj kev tshawb no tsom mus rau tus yam ntxwvnephrotoxicitytom qab ICI pib systematically. Cov ntaub ntawv raug muab rho tawm los ntawm US FDA Adverse Event Reporting System (FAERS) database. Kev soj ntsuam tsis sib xws, suav nrog cov ntaub ntawv cov khoom (ICs) thiab tshaj tawm qhov txawv txav (RORs), tau ua los txiav txim siab txog lub raum toxicity ntawm ICIs. Tag nrho ntawm 7,204 tsab ntawv ceeb toom ntawm lub raum tsis zoo tshwm sim (AEs) tau txheeb xyuas hauv FAERS database. feem ntau tshaj tawm rau nivolumab (46.84%). Cov teeb liab muaj zog tau kuaj pom hauv cov txiv neej cov neeg mob ua ke nrog ICIs. Hauv kev kho mob ntawm ICIs, kev saib xyuas yuav tsum tau them rau cov neeg mob, tshwj xeeb tshaj yog cov neeg mob txiv neej, nrogmob raum raug mob, nephritis, autoimmune nephritis, thiab lwm yam nephrotoxic AEs. Kev siv ICIs yuav ua rau lawv qhov mob hnyav dua.

Ntsiab lus:Cov xwm txheej tsis zoo; Cov Txheej Txheem Tshaj Tawm Tsis Zoo; kev soj ntsuam tsis sib xws;Immune checkpoint inhibitors; nephrotoxicity

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Taw qhia

Immune checkpoint inhibitors (ICIs) yog cov tshuaj tshiab hauv kev kho mob qog noj ntshav. Lawv tau txais koob meej sai rau lawv txoj kev vam meej hauv kev txhim kho cov txiaj ntsig kho mob hauv ntau hom mob qog noj ntshav (Wrangle li al. 2018). Cov chaw kuaj kab mob tiv thaiv kab mob tau tsim cov cell tuag protein 1 txoj hauv kev (PD-1} / PD-L1) thiab cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ​​ua raws li lub luag haujlwm "brake" hauv kev tiv thaiv kab mob thiab qhia. uas tiv thaiv lub cev tiv thaiv kab mob tuaj yeem rov ua haujlwm T hlwb thiab tshem tawm cov qog nqaij hlav cancer zoo (Ljunggren li al. 2018).

Cov ntaub ntawv pov thawj qhia tau tias qhov inhibition ntawm PD-1 txhawb kev tiv thaiv kab mob tiv thaiv kab mob qog noj ntshav (Messenheimer li al. 2017). Tsis tas li ntawd, kev txhim kho ntawm PD-L1 checkpoint inhibitors tau hloov cov toj roob hauv pes uas tsis yog-hlwb-hlwb mob ntsws cancer (NSCLC) kho, nrog 2 kev pom zoo los ntawm US Food and Drug Administration (FDA) ntawm PD-1 inhibitors rau Kev kho thib ob (Sacher thiab Gandhi 2016). Hais txog kev kho mob tshwm sim ntawm CTLA{10}}, thawj kab kev kho mob nrog nivolumab ntxiv rau ipilimumab tau ua rau lub sijhawm ntev ntawm tag nrho cov ciaj sia taus ntau dua li cov kws khomob hauv cov neeg mob NSCLC, ywj pheej ntawm PD-L1 qhia theem (Hellmann li al. 2019 ).

Txawm li cas los xij, kev pheej hmoo ntawm cov xwm txheej tsis zoo (AEs) ntawm ICIs tau nyiam cov kev coj ua hauv kev kho mob.Nephrotoxicityyog ib qho AE ubiquitous. Nws yuav ua rau muaj xwm txheej loj thiab tuag taus yog tias kws kho mob tsis paub thiab kho nws sai. Cov xwm txheej tsis zoo rau lub raum tsis tshua muaj tshwm sim, nrog kwv yees li ntawm 2% nrog cov tshuaj tiv thaiv PD{-1/PD-L1 thiab 5% nrog kev sib xyaw ua ke hauv kev tshuaj xyuas theem 2 thiab 3 kev sim, tab sis kev tshawb fawb tsis ntev los no. tau hais tias qhov xwm txheej ntawmmob raum raug mobyog siab tshaj qhov uas tau tshaj tawm thawj zaug (Li et al. 2021).

Nyob rau hauv txoj kev tshawb no, ib qho kev soj ntsuam tsis sib haum xeeb tau ua rau tus cwj pwm thiab ntsuas nephrotoxicity cuam tshuam nrog ICI kev tswj hwm siv AE cov ntaub ntawv hauv FDA Adverse Event Reporting System (FAERS) database. Txawm hais tias cov ntaub ntawv hauv FAERS cov ntaub ntawv yuav tsis muaj cov ncauj lus qhia ntxaws ntxaws, txoj hauv kev no tuaj yeem pab tshawb pom cov koom haum tshuaj lom neeg muaj peev xwm.

Cov ntaub ntawv thiab cov txheej txheem

Tshawb nrhiav kev tsim thiab cov ntaub ntawv

Qhov kev rov qab los no, kev tshawb fawb tshuaj pharmacovigilance yog qhov kev soj ntsuam tsis zoo raws li FAERS cov ntaub ntawv, sau cov ntawv ceeb toom ntawm AEs los ntawm cov neeg siv khoom, cov kws kho mob, cov tuam txhab tshuaj, thiab lwm yam. Nws tso cai rau cov teeb liab tshawb pom thiab qhov muaj pes tsawg leeg ntawm kev sib koom ua ke ntawm cov tshuaj thiab cov ntawv ceeb toom ntawm AEs (Min et al. 2018). Cov ntaub ntawv tawm tswv yim rau txoj kev tshawb fawb no tau muab los ntawm pej xeem tso tawm ntawm FAERS cov ntaub ntawv, suav nrog lub sijhawm txij li thawj peb lub hlis twg xyoo 2013 txog rau lub quarter thib ob ntawm 2020.

Txheej txheem

Cov tshuaj tau kawm suav nrogtshuaj tiv thaivtargeting PD-1 (nivolumab thiab pembrolizumab), PD-L1 (atezolizumab, nivolumab, thiab durvalumab), thiab CTLA-4 (ipilimumab thiab tremelimumab). Cov npe dav dav thiab cov npe hom tau siv los txheeb xyuas cov ntaub ntawv cuam tshuam nrog ICIs vim tias tsis muaj cov txheej txheem coding zoo rau cov tshuaj.

Txoj kev tshawb no suav nrog txhua yam mob raum (tsis suav nrog nephropathies) (Cov Lus Qhia Kho Mob rau Kev Tswj Xyuas Kev Ua Haujlwm (MedDRA) code 10038430) thiab tag nrho cov nephropathies (MedDRA code 10029149) raws li MedDRA version 23.0. Hauv FAERS cov ntaub ntawv, txhua daim ntawv tshaj tawm tau sau npe siv cov lus nyiam (PTs) los ntawm MedDRA, cov lus siv kho mob thoob ntiaj teb tsim los ntawm International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

Kev txheeb cais

Disproportionality tshwm sim thaum cov tshuaj txuam nrog ib qho tshwj xeeb AE hauv kev tshawb fawb pharmacovigilance. Ob-los ntawm-ob lub rooj sib tham tau siv los suav cov ntawv ceeb toom AE ntawm cov tshuaj xav tau thiab lwm yam tshuaj (Table 1). Ob txoj hauv kev tshawb nrhiav cov ntaub ntawv, qhia txog qhov sib txawv ntawm qhov sib txawv (RORs) thiab Bayesian kev ntseeg siab tshaj tawm neural networks (BCPNNs) ntawm cov ntaub ntawv cov khoom (ICs), tau siv los xam qhov tsis sib xws.

ROR tuaj yeem hais tau raws li (Stricker thiab Tijssen 1992)

Tus qauv yuam kev ntawm ln (ROR) thiab 95% kev ntseeg siab lub sijhawm tuaj yeem suav los ntawm

BCPNN thiab nws qhov sib txawv tuaj yeem suav tau raws li (Weinstein li al. 2009)

thiab ij {{0}}, i=1,=2, j=1, thiab=2; C yog tag nrho cov ntaub ntawv qhia hauv cov ntaub ntawv, Cij yog tus naj npawb ntawm kev sib txuas ntawm cov tshuaj ICI (i) thiab cov tshuaj tiv thaiv nephrotoxicity (j), Ci yog tag nrho cov ntaub ntawv qhia txog cov tshuaj ICI (i) hauv cov ntaub ntawv thiab Cj yog tag nrho cov ntaub ntawv qhia txog cov tshuaj tiv thaiv nephrotoxicity (j) hauv cov ntaub ntawv. Lub teeb liab tau suav tias yog qhov tseem ceeb yog tias qhov qis qis ntawm 95% kev ntseeg siab lub sijhawm (ROR025) siab dua 1, lossis yog tias qhov qis kawg ntawm 95% kev ntseeg siab lub sijhawm ntawm cov ntaub ntawv tivthaiv (IC025) ntau dua 0. Tag nrho cov kev soj ntsuam tau ua tiav. nrog SAS version 9.4 thiab R version 3.6.3. Kev pom zoo rau kev coj ncaj ncees thiab kev tso cai los koom tsis tau.

Cov txiaj ntsig

Kev piav qhia

Tag nrho ntawm 52,583,692 cov ntaub ntawv los ntawm FAERS cov ntaub ntawv tau koom nrog hauv txoj kev tshawb no, thiab 7,204 tsab ntawv ceeb toom yog AEs ntawm nephrotoxicity tom qab kho nrog ICIs. Cov yam ntxwv kho mob ntawm cov neeg mob nrograum toxicity using ICIs are shown in Tables 2 and 3. Among all reports of nephrotoxicity associated with ICIs, the proportion of males was larger than that of females (63.66% vs. 29.96%). With further analysis, the signal was also detected (ROR025 = 2.32, IC025 = 0.49). Among all reports of nephrotoxicity associated with each ICI, the signal of males was larger than that of females (Table 4). Significant differences existed between different age groups, too. The proportion of the elderly (>65) yog loj dua cov uas tsis yog neeg laus (< 65) (51.94% vs. 33.94%), and the difference was significant (ROR025 = 1.12, IC025 = 0.04), which might be attributed to the degenerative change of the elderly. The most frequently reported severe outcomes were other serious medical events and hospitalization. Hospitalization (ROR025 = 2.18, IC025 = 0.79), death (ROR025 = 1.50, IC025 = 0.53), and life-threatening (ROR025 = 2.08, IC025 = 1.01) events associated with renal AEs after ICI treatment were reported, indicating the potentially life-threatening nature of ICI-related nephrotoxicity

Table 2 qhia txog cov yam ntxwv kho mob ntawm cov neeg mob raum toxicity siv ICIs thiab lwm yam tshuaj. Tus naj npawb thiab feem pua ​​yog qhia. * Tus nqi ploj lawm hauv FAERS database. AEs, cov xwm txheej tsis zoo; IC025, qis kawg ntawm 95% kev ntseeg siab ntawm IC; ROR025, qis qis ntawm 95% kev ntseeg siab lub sijhawm ntawm ROR; Cov hlwb khoob; tsis muaj ntaub ntawv txaus los xam.

Txawm li cas los xij, qhov sib txawv ntawm ntau yam tshwj xeeb nephrotoxic AEs tau pom nyob rau hauv tag nrho cov txheej txheem ICI. Ntawm tag nrho cov lus ceeb toom ntawm AEs ntawm nephrotoxicity, mob raum raug mob (2,404, 33.37%), lub raum tsis ua haujlwm (1,128, 15.66%), lub raum tsis zoo (778, 10.8%), tubulointerstitial nephritis (617, 8.56%), nephritis (617, 8.56%), 4. Cov ntawv ceeb toom no suav txog 77.47% ntawm tag nrho cov ntawv ceeb toom. Lwm cov lus ceeb toom ntawm AEs ntawm nephrotoxicity yog suav tias tsis tshua muaj.

Lub spectrum ntawm nephrotoxicity AEs txawv nyob rau hauv immunotherapy regimens

Feem ntau, ICIs tsis tshua txuam nrog raum AEs. Thaum soj ntsuam ntxiv lawm, muaj qhov sib txawv tseem ceeb ntawm AEs ntsig txog nephrotoxicity thiab atezolizumab tag nrho (IC025: 0.05; ROR025: 1.04), tab sis tsis yog Lwm yam ICIs (Table 6). Kaum ib nqe lus nyiam (PTs) tau cuam tshuam nrog kev kho mob atezolizumab, xws li pyelonephritis (ROR025=1.20, IC025=0.07) mus rau glomerulonephritis ntev (ROR025=51.95, IC{ {13}}.17). Nivolumab yog nrog qhov dav tshaj plaws ntawm lub raum AEs nrog 26 PTs kuaj pom raws li cov cim, xws li los ntawm anuria (ROR025=1.02, IC025=−0.03) mus rau autoimmune nephritis (ROR025=29.03) , IC025=3.46). Nees nkaum ib PTs tau cuam tshuam nrog kev kho mob pembrolizumab, xws li los ntawm lub raum tubular necrosis (ROR025=1.06, IC025=0.04) mus rau lub raum tsis zoo (ROR025=185.22) , IC025=1.69). Cuaj PTs tau cuam tshuam nrog kev kho ipilimumab, xws li nephrotic syndrome (ROR025=1.08, IC025=−0.04) mus rau autoimmune nephritis (ROR025=72.67, IC{{42}) }.77). Rau durvalumab, 7 dis proportionality signals tau kuaj pom, xws li biotic microangiopathy (ROR025= 1.97, IC025=0.77) mus rau autoimmune nephritis (ROR025=18.27, IC{{51} }}.72). Ib tug me me ntawm lwm cov teeb liab tau tshaj tawm. Tab sis qee qhov teeb meem muaj zog heev tau pom. Avelumab muaj zog ntau txuam nrog pyelonephritis (ROR025=5.27, IC025=1.17). Cemiplimab muaj zog ntau dua nrog rau autoimmune nephritis (ROR025=375.35, IC025=0.83) thiab kev hloov raum raum (ROR025=13.22, IC025=0.20) . Tremelimumab muaj zog ntau cuam tshuam nrog nephritis (ROR025=27.90, IC025=2.83), thiab lwm yam (Daim duab 1 thiab 2).